Inclusion Criteria For Trials Research Articles

Association between inflammatory biomarkers and the cognitive response to a multidomain intervention: secondary longitudinal analyses from the MAPT study.

The aim of this study is to evaluate the association of systemic inflammation measured by plasma biomarkers with the change in cognitive function among participants from the Multidomain Alzheimer Preventive Trial (MAPT) exposed to the multidomain intervention (MI). Secondary analysis of the MAPT longitudinal data. MAPT is a randomized, placebo-controlled trial with 3 interventional groups (omega-3 only, MI only, omega-3 plus MI) and a control group. We tested the association of the change in cognitive function with inflammatory biomarkers (tumoral necrosis factor receptor-1 (TNFR1), monocyte chemoattractant protein-1 (MCP1), Growth Differentiation Factor-15 (GDF15), Interleukin-6 (IL6) and C reactive protein (CRP)) using mixed-effects models. A subgroup analysis was performed in those exposed to the MI. The response to the MI was defined as the change in the composite cognitive score over the 2-year clinical follow-up period. by modeling the response to the intervention and identifying "good responders", i.e., those in the 5th quintile of response at the end of the intervention period (2years after the measurement of inflammatory markers). We included 1,527 participants (mean age 75.3, SD = 4.4; 64% female). Higher levels of GDF15 and TNFR1 were associated with a worse trajectory in the cognitive composite score in adjusted models. "Good responders" had an estimated mean change in the composite score of 0.051 (SD 0.062) over two years of intervention, compared to -0.136 (SD = 0.111) for the "not-good responders". Higher IL6 levels were associated with a decreased likelihood of being a "good responder" (OR = 0.22, p = 0.018, 95% CI 0.06; 0.78), with similar results for CRP (OR = 0.48, p = 0.009, 95% CI 0.28; 0.84). Higher inflammation was associated with a worse cognitive trajectory among nondemented participants and a lower likelihood of being classified as a "good responder" in those receiving a MI. Further confirmation of these findings could lead to the use of systemic inflammation as inclusion or stratification criteria in prevention trials.

Edridge Green Lecture 2022-demystifying clinical trials and regulatory approvals in drug development.

This article provides a comprehensive overview of clinical trial design and regulatory pathways essential for drug development, specifically in the context of retinal diseases. Key concepts include trial structure, efficacy and safety endpoints, and regulatory expectations from agencies like the FDA. It delves into recent regulatory advancements, such as the inclusion of low-luminance vision as a secondary endpoint and analyses case studies from age-related macular degeneration (AMD) trials. Approvals for key retinal drugs, such as ranibizumab and aflibercept, treatments for AMD and diabetic macular oedema, are discussed highlighting criteria like the 15-letter gain/loss in visual acuity as approvable/clinical meaningful efficacy endpoints. Insights into geographic atrophy (GA) and diabetic retinopathy trials showcase the evolving landscape, where anatomical endpoints and new drugs bring fresh challenges and opportunities. It also emphasizes the importance of academic-industry collaboration, citing instances of gene therapy development and innovative endpoint measures like the Multi-Luminance Mobility Test for retinal dystrophies. The overarching aim of this lecture was to demystify the process that spans the design of clinical trials to regulatory approval of drugs so that clinicians understand these complexities. In particular, it is important to understand the reasons behind selection of trial design, inclusion and exclusion criteria, primary and secondary efficacy endpoints and safety endpoints. Since this lecture, there have been important changes in this field including new guidance from the Food and Drug Administration (FDA) as well as lessons learnt from recent drug approvals that are included in this manuscript.

Exploring a novel outcome measure of symptom progression in knee osteoarthritis utilizing a large randomized trial.

Explore a newly defined composite measure of symptom progression for knee osteoarthritis (KOA) in a large, randomized study of a potential disease-modifying osteoarthritis drug (DMOAD). Using longitudinal KOA studies, a potential composite endpoint of time to symptom progression was defined as the first occurrence of worsening ofWestern Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain of ≥10 points with no improvement (≤9 point decrease) in WOMAC Function (0-100 scale). A post hoc analysis explored discrimination and association with structural outcomes in the sprifermin FORWARD trial through Years 3 and 5. All treatment arms of the intent-to-treat population were analyzed. Among the 549 FORWARD participants, 442 (80.5%) completed Year 3, and 378 (68.9%) completed Year 5. Sprifermin showed dose-dependent benefits in the time to symptom progression at Year 3 with hazard ratio (95% CI) for each sprifermin treatment arm vs placebo as follows: 100μg every 6 months (Q6M), 0.51 (0.28, 0.93); 100μg Q12M, 0.69 (0.40, 1.20); 30μg Q6M, 0.89 (0.53, 1.50); and 30μg Q12M, 0.80 (0.47, 1.35). Similar findings were seen through Year 5 and for a subgroup based on modern clinical trial inclusion criteria. There were increased numbers of knee replacements in symptom progressors (n=8, 5.6%) vs non-progressors (n=7, 1.7%). The symptom progression endpoint discriminated between placebo and treatment responses in a post hoc analysis of a Phase 2 investigational DMOAD KOA trial. The endpoint requires validation and further exploration in DMOAD clinical trials. NCT01919164.

Abstract 4125667: National Estimates of Patient Eligibility for Renal Denervation Therapy Post-FDA Approval

Background: Renal denervation (RDN) has been shown in randomized trials to improve blood pressure compared with a sham procedure. Currently, there are two FDA-approved RDN devices in the United States (US). While nearly half of the US population has hypertension (HTN), the number of patients who may benefit from RDN therapy remains uncertain. In this study, we used a nationally representative dataset to approximate the proportion of patients with HTN who may be eligible for consideration of RDN based on selective criteria. Methods: All adult patients with HTN who participated in the National Health and Nutrition Examination Survey (NHANES) between the years 2009-2020 were identified. We characterized the proportion of these participants that met eligibility criteria based on 1) the FDA indication, 2) the SCAI 2023 RDN position statement, and 3) enrollment criteria from the RDN on-medication randomized trials. National estimates were obtained utilizing survey weighting from the NHANES multistage probability survey design. Results: In total, we identified 16,677 patients with HTN in the US, representing a weighted total of 113,786,149 patients ( Table ). Using the FDA indication, 31.6% (95% CI, 30.7%-32.6%) of patients meet eligibility criteria for RDN, corresponding to 35,988,870 US adults. By the SCAI 2023 position statement selection criteria, 21.5% (95% CI, 20.7%-22.3%) of patients are eligible for consideration of RDN. Based on enrollment criteria from the RDN on-medication randomized trials, 2.05% (95% CI, 1.81%-2.33%) of US adults meet eligibility for consideration of RDN ( Figure ). Conclusions: Our findings indicate that nearly one third of US adults with HTN are eligible for consideration of RDN based on the FDA indication; however, a smaller proportion of patients would be eligible based upon society recommendations and randomized trial inclusion criteria. Future studies are needed to further inform which patients will best benefit from this intervention.

NIMG-48. MEASURABLE DISEASE AS BASELINE CRITERION FOR RESPONSE ASSESSMENT IN GLIOBLASTOMA TRIALS – A COMPARATIVE STUDY OF MRI-BASED (RANO 2.0) VERSUS PET-BASED (PET RANO 1.0) ASSESSMENT

Abstract Response assessment in glioblastoma relies on measuring contrast enhancement on MRI according to RANO 2.0 criteria, and ‘measurable disease’ often serves as inclusion criterion for clinical trials. Recently, criteria based on amino acid PET have been proposed for response assessment in clinical trials (PET RANO 1.0). Here, we compare ‘measurable disease’ as defined by PET RANO 1.0 with the standard MRI-based RANO 2.0 criteria in glioblastoma patients. In this retrospective single-center study, we identified patients with newly diagnosed IDH-wildtype glioblastoma who underwent [18F]FET PET and MRI after resection or biopsy and before chemoradiotherapy. Two independent investigators analyzed ‘measurable disease’ according to PET RANO 1.0 versus MRI-based RANO 2.0 criteria. Additionally, lesion size and uptake intensity, including maximal and mean target-to-background ratio, were assessed. We evaluated 136 patients with 76 cases after biopsy and 60 after microsurgical resection. Using RANO 2.0, 35/76 patients (46.1%) had measurable disease in the biopsy group, and 25/60 (41.6%) in the resected group (median sum of maximum cross-sectional diameters: 39.7mm and 28.0mm, respectively). Utilizing PET RANO 1.0, a significantly higher proportion (overall 123/136, 90.4%; 66/76 (86.8%) after biopsy; 57/60 (95.0%) after resection) had measurable disease (p<0.001). None of the 10 patients in the biopsy group nor of the 3 patients in the resected group without measurable disease on PET had measurable disease on MRI. Contrariwise, 32/41 patients (73.2%) in the biopsy group and 30/35 (85.7%) in the resected group without measurable disease on MRI exhibited measurable disease on PET. PET RANO 1.0 identifies a significantly higher number of patients with ‘measurable disease’ compared to conventional MRI-based criteria in the perioperative period of glioblastoma. PET-based assessment may thus serve as a novel baseline parameter for evaluating treatment response in glioblastoma trials, that may allow the enrollment of larger patient populations. Further validation in prospective trials is warranted.

Impact of Structural Severity on Outcomes in Knee Osteoarthritis: An Analysis of Data from Phase 2 and Phase 3 Lorecivivint Clinical Trials.

Developing knee osteoarthritis (OA) treatments is challenging due to assessing pain and joint structure outcomes within a highly heterogeneous disease. Lorecivivint (LOR), an intra-articular (IA) CLK/DYRK inhibitor, modulates Wnt and inflammatory pathways. This review analysis of LOR 0.07 mg trial data aims to describe the potential impact of baseline joint structure on OA pain response. Two Phase 2 and two Phase 3 trials enrolled knee OA patients with Kellgren-Lawrence (KL) Grades 2-3 and Pain Numeric Rating Scale (NRS [0-10]) ≥4 to ≤ 8 in target knee. Cumulative frequency distribution plots by KL grade summarized the percentages of patients with medial joint space width (medial JSW) < 3 mm. Osteoarthritis Research Society International Joint Space Narrowing grades and treatment responses in trials capturing Pain NRS were similarly summarized. Pain outcome changes were estimated using baseline adjusted ANCOVA. Compared with phase 2 trials, the phase 3 trials had an increased proportion of patients with baseline medial JSW < 3 mm. LOR demonstrated beneficial treatment effects vs placebo in KL 2 subgroups, which were found to have higher proportions of baseline medial JSW > 3 mm, apart from one Phase 3 trial with advanced structural knee OA. Baseline medial JSWs were heterogeneous across trials despite KL inclusion criteria. LOR demonstrated greater symptomatic improvements in patients with less structurally advanced disease, indicative of an association between OA structural damage and pain. Early treatment interventions may improve outcomes and provide insight for future OA trial inclusion criteria development. OA-02, NCT02536833; OA-04, NCT03122860; OA-10, NCT04385303; OA-11, NCT03928184.

Real-world eligibility for GLP1-ra therapy in a cohort of heart failure patients

Abstract Background GLP1-ra have demonstrated substantial cardiovascular (CV) benefits in diabetic and, more recently, non-diabetic patients, however their use in heart failure (HF) patients is still limited. Purpose To evaluate real-word eligibility to GLP1-ra in a cohort of HF patients. Methods Demographic and clinical data from HF patients evaluated at a single center HF unit from August 1st 2021 to November 29th 2023 were automatically retrieved from the electronic health record (EHR). Patients were deemed eligible to GLP1-ra based on (1) absence of ongoing treatment with GLP1-ra and (2) either having type 2 diabetes mellitus (T2DM) or satisfying the inclusion criteria of the SELECT trial or those of the STEP-HFpEF trial, which were adapted according to the available information. A sensitivity analysis lowering the body mass-index cut-off to &amp;gt;= 27 kg/m2 also for the STEP-HFpEF trial was performed. Results 1754 patients with an established diagnosis of HF were included; median age was 78.3 (IQR 70.7-83.8) years and 697 patients were female (39.7%). 6 patients had type 1 diabetes mellitus. Among the remaining 1749 patients, 633 (36.2%) patients had T2DM and 14 were already treated with GLP1-ra. Among 1116 patients without diabetes, 302 (27.1%) were eligible to receive GLP1-ra according to the inclusion criteria of the SELECT or STEP-HFpEF trials. 226 (20.2%) satisfied the SELECT trial inclusion criteria and among them 100 (44.8%) had HF with reduced ejection fraction, whereas 136 patients (12.2%) were eligible to receive GLP1-ra according to the STEP-HFpEF trial. Changing the BMI cut-off to &amp;gt;= 27 kg/mq, as in the SELECT trial, 219 patients (19.6%) according to the STEP-HFpEF inclusion criteria and 344 (30.8%) overall were found to be eligible for GLP1-ra therapy. Conclusion Real-word eligibility to GLP1-ra may reach up to 55% of HF patients according to diabetes status or trial inclusion criteria.

PRISM: Patient Records Interpretation for Semantic clinical trial Matching system using large language models

Clinical trial matching is the task of identifying trials for which patients may be eligible. Typically, this task is labor-intensive and requires detailed verification of patient electronic health records (EHRs) against the stringent inclusion and exclusion criteria of clinical trials. This process also results in many patients missing out on potential therapeutic options. Recent advancements in Large Language Models (LLMs) have made automating patient-trial matching possible, as shown in multiple concurrent research studies. However, the current approaches are confined to constrained, often synthetic, datasets that do not adequately mirror the complexities encountered in real-world medical data. In this study, we present an end-to-end large-scale empirical evaluation of a clinical trial matching system and validate it using real-world EHRs. We perform comprehensive experiments with proprietary LLMs and our custom fine-tuned model called OncoLLM and show that OncoLLM outperforms GPT-3.5 and matches the performance of qualified medical doctors for clinical trial matching.

Diagnostic alignment to optimize inter-rater reliability among lung transplant pathologists

BackgroundPoor agreement among lung transplant pathologists has been reported in the assessment of rejection. In addition to acute rejection (AR) and lymphocytic bronchiolitis (LB), acute lung injury (ALI) and organizing pneumonia (OP) were recently identified as histopathologic risk factors for chronic lung allograft dysfunction (CLAD). Therefore, maximizing inter-rater reliability (IRR) for identifying these histopathologic risk factors is important to guide individual patient care and to support incorporating them in inclusion criteria for clinical trials in lung transplantation. MethodsNine pathologists across eight North American lung transplant centers were surveyed for practices in the assessment of lung transplant transbronchial biopsies. We conducted seven diagnostic alignment sessions with pathologists discussing histomorphologic features of CLAD high-risk histopathology. Then, each pathologist blindly scored 75 digitized slides. Fleiss’ kappa, accounting for agreement across numerous observers, was used to determine IRR across all raters for presence of any high-risk finding and each individual entity. ResultsIRR (95% confidence intervals) and % agreement for any high-risk finding (AR, LB, ALI and/or OP) and each individual finding is as follows: Any Finding, k = 0.578 (0.487, 0.668), 78.9%; AR, k = 0.582 (0.481, 0.651), 79.1%; LB, k = 0.683 (0.585, 0.764), 83.5%; ALI, k = 0.418 (0.312, 0.494), 70.9%; OP, k = 0.621 (0.560, 0.714), 81.0%. ConclusionsAfter pre-study diagnostic alignment sessions, a multi-center group of lung transplant pathologists seeking to identify histopathology high-risk for CLAD achieved good IRR.

Infrequent Resolution of Vaso-Occlusive Crises in Routine Clinical Care Among Patients Mimicking the Exa-Cel Trial Population: A Cohort Study of Medicaid Enrollees.

The CRISPR-based gene editing therapy exagamglogene autotemcel (exa-cel) recently received FDA approval for patients with severe sickle cell disease (SCD). The approval was based on a phase III trial (CLIMB SCD 121), which showed 97% efficacy of this treatment in eliminating vaso occlusive crises (VOCs) for 12 consecutive months. To help contextualize results from this trial, we aimed to investigate the proportion of patients with severe SCD who remain VOC-free for a 1-year period in routine clinical care. Using Medicaid claims data (2000-2018), we identified a cohort of patients, 12-35 years old with severe SCD, defined by ≥ 2 VOCs per year for 2 consecutive years, who met other exa-cel trial inclusion criteria to mimic a trial-like population. A VOC was identified using ICD diagnosis codes during hospitalization and ER visits. The primary outcome was the proportion of patients with no VOCs during a 1-year follow-up. A total of 7,425 patients with severe SCD [mean (SD) age: 20.5 (6.0) years, 54.6% females, 84% African Americans], had a mean of 5.2 VOCs, 5.1 ER visits and 3.5 hospitalizations per year during the baseline period. The proportion of patients with no VOCs during the 1-year follow-up was 7.7% (95% confidence interval: 7.1%-8.3%). In conclusion, less than one in 12 patients with severe SCD achieved VOC-free status within 1 year in routine clinical care. These findings suggest that the high efficacy observed for exa-cel in the trial, if replicated in routine clinical care, could translate into a significant public health impact.

Cryoablation of Primary Breast Cancer in Patients Ineligible for Clinical Trials: A Multiinstitutional Study.

BACKGROUND. Breast cancer cryoablation clinical trials have strict inclusion criteria that exclude patients with potentially treatable disease. OBJECTIVE. The purpose of this study was to evaluate the safety and outcomes of breast cancer cryoablation without surgical excision in patients ineligible for prospective cryoablation clinical trials due to unfavorable patient or tumor characteristics. METHODS. This retrospective study included women who underwent cryoablation of biopsy-proven unifocal primary breast cancer with locally curative intent, without surgical excision, despite being ineligible for (and thus excluded from) cryoablation clinical trials, across seven institutions between January 1, 2000, and August 26, 2021. Adverse events (AEs) were recorded. Cryoablation procedures were classified as technically successful if they were not prematurely terminated and achieved intended treatment parameters and if the first follow-up imaging examination showed no evidence of residual disease. The results of follow-up biopsies were recorded. Ipsilateral breast tumor recurrences (IBTRs) diagnosed during follow-up were identified and classified as true recurrence or new primary disease. A competing-risk model was used to estimate the cumulative incidence of IBTR accounting for death before IBTR as a competing risk. RESULTS. The final study sample included 112 patients (median age, 71 years). A total of seven of 112 (6.3%) patients had a minor AE; no moderate or major AEs occurred. A total of 110 of 112 cryoablation procedures (98.2%) were technically successful. During a median follow-up of 2.0 years, 22 of 110 patients (20.0%) underwent biopsy for suspicious imaging findings in the ipsilateral breast, which yielded benign concordant findings in nine of 22 patients (40.9%) and IBTR in 12 of 22 patients (54.5%). Overall, 12 of 110 patients (10.9%) experienced IBTR, including seven with true recurrence and five with new primary disease; three of 12 patients (25.0%) with IBTR had received earlier adjuvant or neoadjuvant therapy. When death was accounted for as a competing risk, the cumulative incidence of IBTR was 5.3%, 12.2%, and 18.2% at 1, 2, and 3 years, respectively. CONCLUSION. In select individuals with unfavorable patient or tumor characteristics, breast cancer cryoablation provides a safe alternative to surgery and has good outcomes. These findings may be particularly relevant in patients who are also poor surgical candidates. CLINICAL IMPACT. Breast cancer cryoablation can be safely applied in a larger patient populations than those defined by clinical trial inclusion criteria.

Feasibility, Safety, and Factors Predicting Completion of CROSS Protocol–Based Neoadjuvant Chemoradiotherapy for Esophageal Squamous Carcinoma: Experience from an Indian Tertiary Care Cancer Center

Background Neoadjuvant chemoradiotherapy (NACRT) using the ChemoRadiotherapy for Oesophageal cancer followed by Surgery Study (CROSS) protocol has improved esophageal cancer outcomes. This study reports the real-world experience of the CROSS regimen for esophageal squamous cell carcinoma (ESCC) regarding its feasibility, safety, and predictors of treatment completion from an Indian tertiary center. Methodology A retrospective review was conducted for patients with ESCC receiving CROSS (radiation dose: 41.4 Gy) or a modified CROSS (mCROSS; radiation dose: 45 Gy) protocol NACRT between 2015 and 2022. We studied the treatment tolerability, factors predicting NACRT completion, and the effect of completion of its chemotherapy component on the pathological outcomes. Results Of the109 patients (68.8% males; mean age, 56 ± 9 years; Charlson's comorbidity index [CCI] &gt;2, 19.3%; stage III–IVA, 58%; mean tumor length, 5.5 ± 2.1cm; CROSS, 70.6%; mCROSS, 29.4%), all except 4 completed radiotherapy but only 58 (53.2%) patients completed ≥4 cycles of chemotherapy. Forty-nine patients belonged to the “extended” CROSS trial inclusion criteria. Among the 60 patients who fulfilled the CROSS inclusion criteria, only 51.7% were able to complete ≥4 chemotherapy cycles. The commonest reason for noncompletion of chemotherapy was the occurrence of neutropenia (60.8%). Pretreatment hemoglobin (≥12 vs. &lt;12 g%; odds ratio [OR]: 2.76; 95% confidence interval [CI]: 1.10–6.96; p = 0.031), a low CCI (≤2 vs. &gt;2; OR: 2.98; 95% CI: 1.02–8.73; p = 0.047), and radiation therapy techniques (conformal vs. conventional; OR: 3.29; 95% CI: 1.14–9.50; p = 0.028) were associated with completion of chemotherapy (≥4 cycles). Although there was a trend toward improved R0 resection (95.7 vs. 91.4%), reduced node positivity (17.0 vs. 31.4%), and a high pCR (57.4 vs. 48.6%) in patients completing chemotherapy (≥4 cycles) compared with those not completing chemotherapy (&lt;4 cycles), these differences were statistically nonsignificant. Conclusion In this study, ESCC patients receiving the CROSS protocol NACRT could complete their radiotherapy component, but a significant proportion exhibited poor chemotherapy tolerance. Neutropenia was a major factor limiting chemotherapy delivery, but anemia, high CCI, and conventional radiation techniques were also associated with noncompletion of chemotherapy. The omission of a few chemotherapy cycles had no significant effect on the pathological response; however, its impact on cancer survival requires further evaluation.

Novel Treatment Strategies for Low-Risk Metastatic Castration-Sensitive Prostate Cancer.

The treatment strategy for metastatic castration-sensitive prostate cancer (mCSPC) has changed significantly in recent years. Based on various guidelines, an upfront androgen receptor signaling inhibitor (ARSI) is the first choice, but in patients of Asian descent, including Japanese patients, there are a certain number of cases in which androgen deprivation therapy (ADT) and CAB are more effective. If patients can be identified who show a marked response to ADT within 12 weeks after the initiation of ADT, which is the inclusion criterion for ARSI clinical trials targeting mCSPC, it would be valuable from an economic standpoint. A total of 218 patients with pure prostate adenocarcinoma and treated with ADT at the Kanazawa University Hospital between January 2000 and December 2020 were included in this study. As a risk classification for mCSPC, in addition to the LATITUDE and CHAARTED criteria, we used the castration-sensitive prostate cancer classification proposed by Kanazawa University (Canazawa), developed by the Department of Urology of Kanazawa University. The Canazawa classification was based on three factors: Gleason pattern 5, bone scan index (BSI) ≥ 1.5, and lactate dehydrogenase (LDH) ≥ 300 IU/L. It defined patients with one factor or less as low-risk and patients with two or three factors as high-risk. The overall survival (OS) and time to castration resistance (TTCR) were estimated retrospectively using the Kaplan-Meier method, and factors associated with TTCR were identified using univariate and multivariate analyses. The median follow-up period was 40.4 months, the median OS period was 85.2 months, and the median TTCR period was 16.4 months. The Canazawa risk classification provided the clearest distinction between the OS and TTCR in mCSPC patients. Multivariate analysis revealed a decrease in PSA levels of <95% at 12 weeks after ADT initiation and was a predictor of short TTCR in low-risk, low-volume patients across all risk classifications. The Canazawa classification differentiated the prognosis of mCSPC patients more clearly. A PSA reduction rate of <95% at 12 w after starting ADT in low-risk, low-volume patients of all risk classifications was significantly shorter than the TTCR. We propose a new treatment strategy, in which patients with low-risk mCSPC are treated with ADT and switched to ARSIs based on the rate of PSA reduction at 12 w.

Proportion of Patients With Ductal Carcinoma In Situ That Qualify for Observation Criteria Set Forth by Clinical Trials.

The COMET, LORD, and LORIS clinical trials are investigating the role of active surveillance in low-risk ductal carcinoma in situ (DCIS). The objective of this study was to identify the proportion of patients eligible for these trials amongst a cohort of patients treated at our institution. Retrospective chart review was performed of patients diagnosed with DCIS who were treated from 2013 to 2022. Clinical, tumor, and imaging inclusion and exclusion criteria of the aforementioned observation trials were applied to determine the proportion of patients eligible for each trial. Upgrade rate to invasive cancer were examined across all three groups. Of 1223 patients diagnosed with DCIS, applying the criteria of each trial, 245 (20%), 238 (19.4%), and 264 (21.6%) patients were eligible for the COMET, LORD, and LORIS trials, respectively. High-grade DCIS and mass on imaging had the largest impact on exclusion. Nineteen (7.8%) of women who qualified for COMET were upgraded to invasive disease at excision, compared to 18 (7.6%) for LORD, and 19 (7.2%) for LORIS. One in five patients diagnosed with DCIS at our institution would qualify for observation with current trial eligibility. Observation of DCIS may have limited impact on all DCIS patients.

The impact of trial inclusion criteria on outcomes in DLBCL patients treated with R-CHOP in the first line: a Danish nationwide study

Up to 50% of diffuse large B-cell lymphoma (DLBCL) patients are ineligible for participation in clinical trials. Ineligible patients have inferior outcomes, but less is known about the impact of commonly used organ-function-based inclusion criteria on drug efficacy estimates. Data on DLBCL patients treated with CHOP+/-rituximab were retrieved from the Danish Lymphoma Registry. Trial inclusion criteria were extracted from four international DLBCL trials (REMoDL-B, GOYA, POLARIX, and HOVON-84). Differences in overall survival (OS) and 5-year restricted mean survival differences (5 y-RMSDs) between trial eligible and ineligible patients were computed. The effectiveness of adding rituximab to CHOP was quantified by the 5 y-RMSD between CHOP and R-CHOP-treated patients and the impact of individual trial criteria on estimated effectiveness was quantified by Shapley-values. In total, 4,083 R-CHOP-treated and 890 CHOP-treated DLBCL patients were included. Across the trials, 18.6-29.3% of the included R-CHOP-treated patients were deemed ineligible for trial based on organ function and performance status alone. Ineligible patients had significantly worse survival, with adjusted absolute differences in 5-year OS of 9-15%. The impact of individual criteria on the estimated effectiveness of adding rituximab to CHOP was small (Shapley-value range, −2.74-0.31). Using a smaller set of criteria derived from a data-driven approach, the number of eligible patients increased by 16-38% and the 5 y-RMSD increased by 0.7-3.1 months. In conclusion, OS among trial ineligible DLBCL patients is inferior as expected, but relaxing trial criteria would have increased the number of trial participants without making major changes in estimated efficacy for a hypothetical CHOP versus R-CHOP trial. This does not necessarily imply that trial findings based on selected patients are unreliable, as the estimated effectiveness of adding rituximab to CHOP was only slightly affected by omitting selected inclusion criteria.

Real-world prevalence, treatment and survival of “high risk” early breast cancer, with mandatory testing of gBRCA1/2 mutation according to the OlympiA trial inclusion criteria: Data from a population-based registry

BackgroundThe results of the OlympiA study led to the approval of a PARP inhibitor (olaparib) as adjuvant treatment for early breast cancer (eBC) at high risk of relapse in patients with a germline BRCA1/2 mutation (gBRCAm). However, the proportion of patients in routine practice who meet the “high-risk” criteria applied in the OlympiA study, and for whom gBRCAm testing would now be mandatory, remains unknown. Patients and methodsIn this population-based study, we use unique data from the French specialized Côte d'Or Breast and Gynecological Cancer Registry, to assess the real-life proportion, and long-term prognosis of patients treated for eBC between 2005 and 2015 with standard treatment, and at “high risk” of relapse according to the OlympiA trial criteria. ResultsWe included 3483 patients treated for HER2-negative eBC (N = 380 with ER-, and N = 3103 with ER + tumor). We found N = 62 (1.8 %) patients with gBRCA1/2 mutations. A total of 494 patients (14.2 %) were classified as “high risk” according to the Olympia criteria; 55 % with ER-tumors, and 9.1 % with ER + tumors, respectively. Despite more intensive systemic treatments in “high risk” patients, 10-year overall survival was much worse in these “high risk” patients compared to the others: 60.1 % vs 83.8 % in ER-tumors, and 55.4 % vs 84.1 % in ER + tumors. Our estimates of net survival show an even greater difference. ConclusionThis study provides real-life insights into the prevalence and prognosis of patients with high-risk eBC, in a context where the approval of adjuvant olaparib requires careful reorganization of care, so as not to overlook a patient with gBRCAm who could benefit from adjuvant olaparib.

A clinical trial inclusion criteria to enrich for patients presenting with canonical symptom structure in bipolar depression

Clinical drug development in psychiatry is challenging due to heterogeneous patient populations and the uncertainty of measuring neuropsychiatric constructs with symptom rating scales. Here we describe the development and implementation of an enrichment algorithm that identifies canonical versus anomalous symptom presentations, at the individual subject level, based on MADRS ratings obtained at screening and baseline. Data from 5 randomized, placebo-controlled, phase 3 trials in bipolar I disorder was used (N = 2026 subjects and 15,239 MADRS assessments). A variance-covariance difference (VCD) vector was developed to encode individual symptom structure using the 10 items of MADRS from the two sequential assessments. An anomaly score, calculated from each subject's VCD vector was derived by isolation forest to quantify the degree of disparity from the hypothesized canonical item structure. A retrospective application of the algorithm reliably identified a threshold anomaly score above which the psychometric properties of MADRS deteriorate. Consistent with increasing the certainty of MADRS ratings, subjects with a canonical symptom structure at baseline demonstrated greater effect sizes post-baseline in a phase 2 placebo-controlled trial of non-racemic amisulpride (SEP-4199) for bipolar depression, analyzed retrospectively. Our analyses show that the developed algorithm can reduce the symptom structure heterogeneity at baseline and thus improve the measurement certainty of psychiatric symptoms in clinical trials. This novel enrichment method has been prospectively implemented in a Phase 3 clinical study of SEP-4199 and is consistent with regulatory guidelines aimed at increasing the statistical power and lowering patient-burden in clinical trials.Clinical Trials Registry: NCT00868452, NCT00868699, NCT01284517, NCT01986101, NCT03543410, NCT05169710

Ensuring the strict and accurate adherence to inclusion criteria in clinical trials for AMD is crucial.

Ensuring the strict and accurate adherence to inclusion criteria in clinical trials for AMD is crucial.

Cardiovascular event reduction among a US population eligible for semaglutide per the SELECT trial

Our objective was to determine the number of major cardiovascular events (MACE, nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death) and deaths from any cause that could be prevented across varying nationwide uptake of semaglutide 2.4 mg SC weekly for the secondary prevention of cardiovascular disease. Using a nationally representative cross-sectional study of participants in the 2017-2018 and 2019-March 2020 cycles of the National Health and Nutrition Examination Survey in the U.S. (NHANES), we estimated the number of MACE and deaths from any cause potentially prevented over a four-year period among participants meeting SELECT trial inclusion criteria. In a sample of n = 216 individuals (corresponding to 4,473,681 adults in the U.S. population) potentially eligible for this therapy, a total of 356,329 MACE and 232,808 all-cause mortality events were expected without semaglutide over 4 years and 35,633 MACE and 22,117 all-cause mortality events would be prevented with 50% uptake of semaglutide. Approximately 4.5 million adults in the U.S. are forecasted to be eligible for semaglutide 2.4mg SC weekly therapy, with substantial impact on CVD and mortality if accessible and broadly used.

Occupational Stress as A Risk Factor for Hypertension in Oil and Mine Workers: A Systematic Review

Background. Occupational stress is a pervasive concern in the extractive sector, which encompasses oil and mining activities, serving as a potential repercussion for cardiovascular health. Therefore, further studies about the correlation between occupational stress in extractive sector workers and hypertension are needed. This review highlights how occupational stress poses a risk for hypertension in oil workers and miners for better future management. Methods. Studies were extracted mostly from PubMed, using the keywords "occupational stress", "hypertension", "oil workers", and “miners”. The extracted studies were then analyzed and selected according to our inclusion criteria of clinical trials within the last 5 years with subjects working in oil fields or mines. This study excludes meta-analysis, systematic reviews, case reports, and animal studies. The New Castle Ottawa Scale (NOS) was utilized to assess research quality. Only high-quality studies were considered in this analysis. Results. 7 studies were extracted for this review, all are of high quality based on the NOS. The studies used in this review described occupational stress as a risk factor for hypertension in oil or mine workers. Discussion. Two studies showed that the psychological impact of occupational stress leads to hypertension. Other studies showed that strong individual strains, gene mutation, hair cortisol concentration, and lifestyles, such as BMI, leisure-time physical activity (LTPA), and others may also be additional factors that lead to hypertension. Conclusion. Occupational stress poses a risk factor for hypertension in oil and mine workers, taking note also other potential additional factors that may be associated with it.