Patient Enrollment Research Articles

Clinical site selection problems with probabilistic constraints

Recruiting candidates globally and across multiple sites in different geographic regions is necessary to speed up the enrollment of clinical trials. While patient enrollment can benefit from this globalization, initiating clinical trials has become much more complicated. In the start-up stage, the sites must be selected out of a set of potential candidates around the globe based on the specifics of those clinical trials, such as protocols, operational costs, and recruitment deadlines. Sites in one region can be very distinct from sites in another area. Yet, a common mistake in selecting sites is to rely on too little knowledge or subjective data. Poor selection decisions can lead to study delays and prolong the time to market for life-saving treatments. Thus, this paper proposes a novel framework to aid the decision-making in the global site selection problem (GSSP). To ensure that our framework accurately captures the uncertainty in recruitment time, we adopt a risk-based constraint that accounts for random patient enrollment. The extensive computational studies help quantify significant time-cost trade-offs as a potential solution to control the costs of conducting a trial.

Enhancing site selection strategies in clinical trial recruitment using real-world data modeling.

Slow patient enrollment or failing to enroll the required number of patients is a disruptor of clinical trial timelines. To meet the planned trial recruitment, site selection strategies are used during clinical trial planning to identify research sites that are most likely to recruit a sufficiently high number of subjects within trial timelines. We developed a machine learning approach that outperforms baseline methods to rank research sites based on their expected recruitment in future studies. Indication level historical recruitment and real-world data are used in the machine learning approach to predict patient enrollment at site level. We define covariates based on published recruitment hypotheses and examine the effect of these covariates in predicting patient enrollment. We compare model performance of a linear and a non-linear machine learning model with common industry baselines that are constructed from historical recruitment data. Performance of the methodology is evaluated and reported for two disease indications, inflammatory bowel disease and multiple myeloma, both of which are actively being pursued in clinical development. We validate recruitment hypotheses by reviewing the covariates relationship with patient recruitment. For both indications, the non-linear model significantly outperforms the baselines and the linear model on the test set. In this paper, we present a machine learning approach to site selection that incorporates site-level recruitment and real-world patient data. The model ranks research sites by predicting the number of recruited patients and our results suggest that the model can improve site ranking compared to common industry baselines.

How Much More Efficient Are Adaptive Platform Trials Than Multiple Stand-Alone Trials? A Comprehensive Simulation Study for Streamlining Drug Development During a Pandemic.

With the coronavirus disease 2019 (COVID-19) pandemic, there is growing interest in utilizing adaptive platform clinical trials (APTs), in which multiple drugs are compared with a single common control group, such as a placebo or standard-of-care group. APTs evaluate several drugs for one disease and accept additions or exclusions of drugs as the trials progress; however, little is known about the efficiency of APTs over multiple stand-alone trials. In this study, we simulated the total development period, total sample size, and statistical operating characteristics of APTs and multiple stand-alone trials in drug development settings for hospitalized patients with COVID-19. Simulation studies using selected scenarios reconfirmed several findings regarding the efficiency of APTs. The APTs without staggered addition of drugs showed a shorter total development period than stand-alone trials, but the difference rapidly diminished if patient's enrollment was accelerated during the trials owing to the spread of infection. APTs with staggered addition of drugs still have the possibility of reducing the total development period compared with multiple stand-alone trials in some cases. Our study demonstrated that APTs could improve efficiency relative to multiple stand-alone trials regarding the total development period and total sample size without undermining statistical validity; however, this improvement varies depending on the speed of patient enrollment, sample size, presence/absence of family-wise error rate adjustment, allocation ratio between drug and placebo groups, and interval of staggered addition of drugs. Given the complexity of planning and implementing APT, the decision to implement APT during a pandemic must be made carefully.

Management of long bone fractures and traumatic hip dislocations in paediatric patients: study protocol for a prospective global multicentre observational cohort registry

IntroductionManagement controversy and clinical equipoise exist in treatments of long bone fractures and traumatic hip dislocation in paediatric patients due to the lack of high-quality clinical evidence. This protocol describes...

Simplified clinical frailty scale design, validation, and adaptation in older patients.

The clinical frailty scale (CFS) evaluates the level of frailty based on clinical examination, comorbidities, and functional and activity levels of older patients. However, there are many difficulties for internists in evaluating frailty with this scale. Therefore, simplifying the CFS with good design and application is required for better treatment outcomes. Our study was conducted to design and evaluate the correlation of a simplified clinical frailty scale (sCFS) with CFS in older patients. We undertook a cross-sectional analysis involving 279 older patients, which comprised two steps. Step 1 involves the implementation of sCFS, a protocol that has been endorsed by the Geriatrics Professional Council (GPC). Step 2 entails the enrollment of older patients for frailty assessment using sCFS, comparing it with CFS. The study was conducted on 279 older patients; the average age was 75.7 ± 8.4 (years old), and men accounted for 34.8%. There was a high correlation between the sCFS and CFS (Pearson's r = 0.996; p < 0.001). The similarity of the sCFS to the CFS was very high, with Kappa coefficient = 0.984 (p < 0.001). Compared with the CFS, the sCFS had a Youden index of 98% with 100% sensitivity and 98% specificity assessed through the receiver operating characteristic (ROC) with the CFS threshold of 5. The sCFS can be used to assess frailty with high sensitivity and specificity.

Patient Portal Enrollment for Discharged Pediatric Emergency Department Patients: A Multidisciplinary Quality Improvement Project.

Patient portal enrollment following pediatric emergency department (ED) visits allows access to critical results, physician documentation, and telehealth follow-up options. Despite these advantages, there are many challenges to portal invitation and enrollment. Our primary objective was to improve patient portal enrollment rates for discharged pediatric ED patients. A multidisciplinary team of staff from two ED sites developed successful portal enrollment interventions through sequential Plan-Do-Study-Act cycles from October 2020 to October 2021. Interventions included a new invitation process, changes to patient paperwork on ED arrival, staff portal education, and changes to discharge paperwork and the portal website. The team utilized statistical process control charts to track the percentage of eligible discharged patients who received a portal invitation (process measure) and enrolled in the patient portal. Before the study's initiation, less than 1% of eligible patients received patient portal invites or enrolled in the patient portal. Statistical process control charts revealed significant changes in enrollment and baseline shift at both a large academic ED campus and a satellite ED site by May 2021. Improvements in invitation rates were also observed at both campuses. Changes were sustained for over 6 months at both locations. High-reliability interventions and a multidisciplinary approach allowed for significant and sustained improvement in patient portal invitation and enrollment rates in eligible pediatric ED patients. Future study will examine enrollment patterns across patient demographics and further high-reliability interventions.

A novel referral strategy to enhance the enrollment of patients with heart failure in cardiac rehabilitation: A feasibility study.

Rehabilitation targeting patients with cardiac conditions are evident and acknowledged in clinical guidelines. However, participation rates remain suboptimal, with only 50% of all patients with cardiac conditions participating in these programs across Europe. Considering the well-documented effects of rehabilitation, increasing the referral rate to cardiac rehabilitation would be desirable. This study aimed to evaluate the feasibility of a novel referral strategy that could potentially enhance enrollment in cardiac rehabilitation for patients with heart failure. This prospective feasibility study incorporating both quantitative and qualitative methods was conducted in an outpatient heart failure clinic and a municipal health care center. 106 patients with heart failure were referred to the heart failure clinic from September 2021 through July 2022. A 15-20 min face-to-face physiotherapy consultation was incorporated into usual care, evaluating patients' habitual and actual level of functioning, disability, and physical activity and assessing their potential need and motivation for cardiac rehabilitation. Three predefined quantitative feasibility outcomes: reach, referral rate, and data completeness were assessed. Additionally, semi-structured interviews explored acceptability among patients and health care professionals at the municipal health care center and the hospital. Finally, the potential effect was assessed based on the enrollment rate. Physiotherapy consultations were offered to 86% of eligible patients; of these, 52% were referred to cardiac rehabilitation. Ninety-one percent data completeness was achieved. The intervention was well-accepted by patients and health care professionals. The enrollment rate reached 79%. The novel referral strategy proved feasible concerning reach and data completeness, although the referral rate suggested that further refinements are required before a full-scale trial. The novel referral strategy was well-accepted, and enrollment rate approached an acceptable level.

Dipsticks and point-of-care Microscopy to reduce antibiotic use in women with an uncomplicated Urinary Tract Infection (MicUTI): protocol of a randomised controlled pilot trial in primary care

IntroductionUncomplicated urinary tract infections (uUTIs) in women are common infections encountered in primary care. Evidence suggests that rapid point-of-care tests (POCTs) to detect bacteria and erythrocytes in urine at presentation...

Clinical effectiveness of patient-targeted feedback following depression screening in general practice (GET.FEEDBACK.GP): an investigator-initiated, prospective, multicentre, three-arm, observer-blinded, randomised controlled trial in Germany

Screening for depression in primary care alone is not sufficient to improve clinical outcomes. However, targeted feedback of the screening results to patients might result in beneficial effects. The GET.FEEDBACK.GP trial investigated whether targeted feedback of the depression screening result to patients, in addition to feedback to general practitioners (GPs), leads to greater reductions in depression severity than GP feedback alone or no feedback. The GET.FEEDBACK.GP trial was an investigator-initiated, multicentre, three-arm, observer-blinded, randomised controlled trial. Depression screening was conducted electronically using the Patient Health Questionnaire-9 (PHQ-9) in 64 GP practices across five regions in Germany while patients were waiting to see their GP. Currently undiagnosed patients (aged ≥18 years) who screened positive for depression (PHQ-9 score ≥10), were proficient in the German language, and had a personal consultation with a GP were randomly assigned (1:1:1) into a group that received no feedback on their depression screening result, a group in which only the GP received feedback, or a group in which both GP and patient received feedback. Randomisation was stratified by treating GP and PHQ-9 depression severity. Trial staff were masked to patient enrolment and study group allocation and GPs were masked to the feedback recieved by the patient. Written feedback, including the screening result and information on depression, was provided to the relevant groups before the consultation. The primary outcome was PHQ-9-measured depression severity at 6 months after randomisation. An intention-to-treat analysis was conducted for patients who had at least one follow-up visit. This study is registered at ClinicalTrials.gov (NCT03988985) and is complete. Between July 17, 2019, and Jan 31, 2022, 25 279 patients were approached for eligibility screening, 17 150 were excluded, and 8129 patients completed screening, of whom 1030 (12·7%) screened positive for depression. 344 patients were randomly assigned to receive no feedback, 344 were assigned to receive GP-targeted feedback, and 339 were assigned to receive GP-targeted plus patient-targeted feedback. 252 (73%) patients in the no feedback group, 252 (73%) in the GP-targeted feedback group, and 256 (76%) in the GP-targeted and patient-targeted feedback group were included in the analysis of the primary outcome at 6 months, which reflected a follow-up rate of 74%. Gender was reported as female by 637 (62·1%) of 1025 participants, male by 384 (37·5%), and diverse by four (0·4%). 169 (16%) of 1026 patients with available migration data had a migration background. Mean age was 39·5 years (SD 15·2). PHQ-9 scores improved for each group between baseline and 6 months by -4·15 (95% CI -4·99 to -3·30) in the no feedback group, -4·19 (-5·04 to -3·33) in the GP feedback group, and -4·91 (-5·76 to -4·07) in the GP plus patient feedback group, with no significant difference between the three groups (global p=0·13). The difference in PHQ-9 scores when comparing the GP plus patient feedback group with the no feedback group was -0·77 (-1·60 to 0·07, d=-0·16) and when comparing with the GP-only feedback group was -0·73 (-1·56 to 0·11, d=-0·15). No increase in suicidality was observed as an adverse event in either group. Providing targeted feedback to patients and GPs after depression screening does not significantly reduce depression severity compared with GP feedback alone or no feedback. Further research is required to investigate the potential specific effectiveness of depression screening with systematic feedback for selected subgroups. German Innovation Fund. For the German translation of the abstract see Supplementary Materials section.

How we approach early phase clinical trial and off-label therapy consults in pediatric oncology: The New Agents and Innovative Therapy (NAIT) team experience

In the context of hard-to-cure disease, pediatric oncologists may have to explore novel therapy options and explain their rationale, risks and constraints to patients and caregivers. The New Agents and Innovative Therapy (NAIT) program at Hospital for Sick Children in Toronto facilitates patient enrollment in clinical trials as well as access to innovative therapies outside of clinical trials. Here, we summarize our experience with helping patients, caregivers, and their primary oncology team navigate information and access to new therapeutic options through enrollment in clinical trials but also off-label and compassionate use. We expose our approach to exploring clinical trial and other therapy options. We share lessons learned from clinical practice regarding the specific role of NAIT consultant, as opposed to the primary oncologist or the disease expert. We expand on ways to communicate regarding the objectives of early phase clinical trials, their methods and the important commitment asked from participants. We describe our views on equipoise, uncertainty and hope in this very specific practice. We support a model of shared decision making and empowerment of patients and caregivers. We also detail the use, benefits and challenges of virtual care applied to NAIT consults. Overall, we hope to contribute and facilitate the NAIT practice not only for trained trialists but also less-specialized teams.

Exclusion of older patients from randomized clinical trials in Parkinson's disease.

Prevalence of Parkinson's disease (PD) increases with age. The purpose of this study was to evaluate the eligibility criteria in randomized clinical trials (RCTs) in PD, especially those limiting the enrollment of older adults. We examined RCTs of pharmacological and non-pharmacological anti-parkinsonian interventions registered with ClinicalTrials.gov and started from 2013 through 2022. Primary outcome was proportion of RCTs with an upper age limit of 85years of age or less. Secondary outcome was proportion of RCTs with other exclusion criteria. Associations between trial characteristics and the presence of the age limits were determined using logistic regression. Our study included 420 RCTs. Two hundred thirty-nine (57%) of these had an upper age limit of 85years of age or less. Proportion of these trials significantly increased over time. The odds of the presence of an upper age limit were significantly associated with the investigational site location, phase, and timeframe for theprimary endpoint assessment. Three hundred fifty-six (85%) trials had other eligibility criteria limiting the enrollment of older patients; these often (n = 285; 68%) included cognitive impairment. Overall, 386 (92%) RCTs either explicitly excluded older adults or had criteria indirectly limiting their enrollment. Underrepresentation of older patients in clinical trials in PD considerably reduces the generalizability of their results. Some eligibility criteria should be modified to enable the investigators to assess the benefits and harms of new therapeutic interventions in older adults. This problem is important in view of rapidly growing number of older patients with PD.

Assessing the impact of public funding in alleviating participant reduction and improving the retention rate in methadone maintenance treatment clinics in Taiwan: an interrupted time series analysis

Background Given the steady decline in patient numbers at methadone maintenance treatment (MMT) clinics in Taiwan since 2013, the government initiated Patients’ Medical Expenditure Supplements (PMES) in January 2019 and the MMT Clinics Accessibility Maintenance Program (MCAM) in September 2019. This study aims to evaluate the impact of the PMES and MCAM on the enrollment and retention of patients attending MMT clinics and whether there are differential impacts on MMT clinics with different capacities.Methods The monthly average number of daily participants and 3-month retention rate from 2013 to 2019 were extracted from MMT databases and subjected to single interrupted time series analysis. Pre-PMES (from February 2013 to December 2018) was contrasted with post-PMES, either from January 2019 to December 2019 for clinics funded solely by the PMES or from January 2019 to August 2019 for clinics with additional MCAM. Pre-MCAM (from January 2019 to August 2019) was contrasted with post-MCAM (from September 2019 to December 2019). Based on the monthly average number of daily patients in 2018, each MMT clinic was categorized as tiny (1–50), small (51–100), medium (101–150), or large (151–700) for subsequent stratification analysis.ResultsIn terms of participant numbers after the PMES intervention, a level elevation and slope increase were detected in the clinics at every scale except medium in MMT clinics funded solely by PMES. In MMT clinics with subsequent MCAM, a level elevation was only detected in small-scale clinics, and a slope increase in the participant numbers was detected in tiny- and small-scale clinics. The slope decrease was also detected in medium-scale clinics. In terms of the 3-month retention rate, a post-PMES level elevation was detected at almost every scale of the clinics, and a slope decrease was detected in the overall and tiny-scale clinics for both types of clinics.ConclusionsSupplementing the cost of a broad treatment repertoire enhances the enrollment of people with heroin use in MMTs. Further funding of human resources is vital for MMT clinics to keep up with the increasing numbers of participants and their retention.

Safety of Boron Neutron Capture Therapy with Borofalan(10B) and Its Efficacy on Recurrent Head and Neck Cancer: Real-World Outcomes from Nationwide Post-Marketing Surveillance.

This study was conducted to evaluate the real-world safety and efficacy of boron neutron capture therapy (BNCT) with borofalan(10B) in Japanese patients with locally advanced or locally recurrent head and neck cancer (LA/LR-HNC). This prospective, multicenter observational study was initiated in Japan in May 2020 and enrolled all patients who received borofalan(10B) as directed by regulatory authorities. Patient enrollment continued until at least 150 patients were enrolled, and adverse events attributable to drugs, treatment devices, and BNCT were evaluated. The patients with LA/LR-HNC were systematically evaluated to determine efficacy. The 162 patients enrolled included 144 patients with squamous cell carcinoma of the head and neck (SCCHN), 17 patients with non-SCCHN (NSCCHN), and one patient with glioblastoma. Treatment-related adverse events (TRAEs) were hyperamylasemia (84.0%), stomatitis (51.2%), sialoadenitis (50.6%), and alopecia (49.4%) as acute TRAEs, and dysphagia (4.5%), thirst (2.6%), and skin disorder (1.9%) as more common late TRAEs. In patients with LA/LR-HNC, the overall response rate (ORR) was 72.3%, with a complete response (CR) in 63 (46.0%) of 137 patients with SCCHN. Among 17 NSCCHN patients, the ORR was 64.7%, with eight cases (47.1%) of CR. One- and two-year OS rates in patients with recurrent SCCHN were 78.8% and 60.7%, respectively. This post-marketing surveillance confirmed the safety and efficacy of BNCT with borofalan(10B) in patients with LA/LR-HNC in a real-world setting.

Chinese Additive Anti-inflammatory Action for Aortopathy & Arteriopathy (5A)Registry protocol: rationale, design and methodology.

Acute aortic syndrome (AAS) is a life-threatening condition. Inflammation plays a key role in the pathogenesis, development and progression of AAS, and is associated with significant mortality and morbidity. Understanding the inflammatory responses and inflammation resolutions is essential for an appropriate management of AAS. Thirty Chinese cardiovascular centers have collaborated to create a multicenter observational registry (named Chinese Additive Anti-inflammatory Action for Aortopathy & Arteriopathy [5A] registry), with consecutive enrollment of adult patients who underwent surgery for AAS that was started on Jan 1, 2016 and will be ended on December 31, 2040. Specially, the impact of inflammation and anti-inflammatory strategies on the early and late adverse events are investigated. Primary outcomes are severe systemic inflammatory response syndrome (SIRS), multiple organ dysfunction syndrome (MODS), Sequential Organ Failure Assessment (SOFA) scores at 7 days following this current surgery. Secondary outcomes are SISR, 30-day mortality, operative mortality, hospital mortality, new-onset stroke, acute kidney injury, surgical site infection, reoperation for bleeding, blood transfusion and length of stay in the intensive care unit. The analysis of this multicenter registry will allow our better knowledge of the prognostic importance of preoperative inflammation and different anti-inflammatory strategies in adverse events after surgery for AAS. This registry is expected to provide insights into novel different inflammatory resolutions in management of AAS beyond conventional surgical repair. ClinicalTrials.gov Identifier:NCT04398992 (Initial Release: 05/19/2020).

Racial Differences in Hospice Care Outcomes in Patients With Advanced Heart Failure: Systematic Review and Meta-analysis

There remains a paucity of investigational data about disparities in hospice services in people with non-cancer diagnoses, specifically in heart failure (HF). Black patients with advanced HF have been disproportionally affected by health care services inequities but their outcomes after hospice enrollment are not well studied. We aimed to describe race-specific outcomes in patients with advanced HF who were enrolled in hospice services. We obtained the data from PubMed, Scopus, and Embase for all investigations published until January 11, 2023. All studies that reported race-specific outcomes after hospice enrollment in patients with advanced HF were included. Of the 1,151 articles identified, 5 studies (n = 24,899) were considered for analysis involving a sample size ranging from 179 to 11,754 patients. Black patients had an increased risk of readmission (odds ratio 1.55, 95% confidence interval [CI] 1.34 to 1.79, I2 0%) and discharge (odds ratio 1.75, 95% CI 1.53 to 1.99, I2 0%) compared with White patients. Moreover, Black patients have a nonsignificant lower risk of mortality compared with White patients (relative risk 0.67, 95% CI 0.43 to 1.05, I2 90%). In conclusion, this study showed that Black patients with advanced HF receiving hospice care have a higher risk of readmission and discharge compared with White patients.

A311 EFFICACY OF PANCREATIC CANCER SCREENING IN HIGH RISK INDIVIDUALS

Abstract Background Pancreatic cancer (PC) is the 11th most prevalent cancer in Canada with about 6900 new cases in 2021. Due to late diagnosis, it is the 4th largest cause of cancer related mortality in Canada. Despite advances in diagnosis and treatment over the past decade, the 5-year survival remains ampersand:003C10%, making pancreatic cancer one of the most lethal malignancies worldwide. However, if detected early, the 5-year survival increases to 80%. The incidence of pancreatic cancer remains low. Therefore, the International Cancer of the Pancreas Screening (CAPS) consortium do not recommend screening everyone. Selective screening in high-risk individuals may be effective in early detection and treatment of pancreatic cancer. Aims 1. To determine the characteristics of patients undergoing PC screening at a single tertiary care center in Vancouver. 2. To determine the frequency of disease progression and outcomes in patients diagnosed with high-risk lesions during screening. Methods Retrospective chart review was performed for patients who were screened between January 1, 2005 to June 30, 2023. As per consensus from the CAPS Consortium, patients with at least 2 close relatives with PC, and those with predisposing genetic mutations screened using endoscopic ultrasound (EUS) and/or magnetic resonance imaging (MRI) were included in the study. Clinical data, such as age, tobacco use, genetic risk, endoscopic findings, and outcomes, such as disease progression, were collected. Statistical analysis was performed using Rstudio and Microsoft Excel. Results 73 patients were included, with 42 included due to pathogenic germline mutations, and 31 with familial pancreatic cancer. Most were female (52, 71.2%). Median age in the study was 54 years (range 24-74 years) at initial screening. 66 patients (90.4%) received an EUS and 7 patients (9.6%) received MRI for initial screening. At the time of initial screening. 74.6% of patients had a normal pancreas. 6 patients (8.2%) were found to have neoplastic lesions, e.g. ampulloma, neuroendocrine tumour or adenocarcinoma at initial screening and referred for surgery. In the median follow up time of 67.9 months (range 0-168.1 months), 6 patients were noted to have disease progression, 4 of which had increase in cyst size without any other worrisome features. 2 patients had progression to malignancy. 1 of those patients received chemotherapy and surgical resection and remains alive; the other patient was lost of follow up due to geographical move. Conclusions Pancreatic cancer screening in high risk individuals is effective in early detection and treatment. Given lower incidence of pancreatic cancer, we likely need additional patient enrolment to observe a significant improvement in patient outcomes. Funding Agencies None

Endovascular Thrombectomy for Large Ischemic Stroke Across Ischemic Injury and Penumbra Profiles

Whether endovascular thrombectomy (EVT) efficacy for patients with acute ischemic stroke and large cores varies depending on the extent of ischemic injury is uncertain. To describe the relationship between imaging estimates of irreversibly injured brain (core) and at-risk regions (mismatch) and clinical outcomes and EVT treatment effect. An exploratory analysis of the SELECT2 trial, which randomized 352 adults (18-85 years) with acute ischemic stroke due to occlusion of the internal carotid or middle cerebral artery (M1 segment) and large ischemic core to EVT vs medical management (MM), across 31 global centers between October 2019 and September 2022. EVT vs MM. Primary outcome was functional outcome-90-day mRS score (0, no symptoms, to 6, death) assessed by adjusted generalized OR (aGenOR; values >1 represent more favorable outcomes). Benefit of EVT vs MM was assessed across levels of ischemic injury defined by noncontrast CT using ASPECTS score and by the volume of brain with severely reduced blood flow on CT perfusion or restricted diffusion on MRI. Among 352 patients randomized, 336 were analyzed (median age, 67 years; 139 [41.4%] female); of these, 168 (50%) were randomized to EVT, and 2 additional crossover MM patients received EVT. In an ordinal analysis of mRS at 90 days, EVT improved functional outcomes compared with MM within ASPECTS categories of 3 (aGenOR, 1.71 [95% CI, 1.04-2.81]), 4 (aGenOR, 2.01 [95% CI, 1.19-3.40]), and 5 (aGenOR, 1.85 [95% CI, 1.22-2.79]). Across strata for CT perfusion/MRI ischemic core volumes, aGenOR for EVT vs MM was 1.63 (95% CI, 1.23-2.16) for volumes ≥70 mL, 1.41 (95% CI, 0.99-2.02) for ≥100 mL, and 1.47 (95% CI, 0.84-2.56) for ≥150 mL. In the EVT group, outcomes worsened as ASPECTS decreased (aGenOR, 0.91 [95% CI, 0.82-1.00] per 1-point decrease) and as CT perfusion/MRI ischemic core volume increased (aGenOR, 0.92 [95% CI, 0.89-0.95] per 10-mL increase). No heterogeneity of EVT treatment effect was observed with or without mismatch, although few patients without mismatch were enrolled. In this exploratory analysis of a randomized clinical trial of patients with extensive ischemic stroke, EVT improved clinical outcomes across a wide spectrum of infarct volumes, although enrollment of patients with minimal penumbra volume was low. In EVT-treated patients, clinical outcomes worsened as presenting ischemic injury estimates increased. ClinicalTrials.gov Identifier: NCT03876457.

Phase of Illness at the time of being referred to the hospital palliative care team and changes after the intervention

Objective Palliative care is provided according to patient needs. Healthcare providers can use the Phase of Illness to assess patient needs and improve palliative care. However, patients’ phase changes after the palliative care team’s intervention remain unknown. Methods This study clarified the Phase of Illness of patients referred to palliative care teams at hospitals and the changes in their phase after the intervention. Our study was a secondary analysis of a multicenter survey involving patient-reported outcomes. This study was conducted between February and August 2021 at eight facilities with palliative care teams. The participants were patients for whom the palliative care team received a new request for intervention during the patient enrollment period. Results Out of the 310 patients, 68 (21.9%) were in the stable phase, 141 (45.5%) in the unstable phase, 87 (28.1%) in the deteriorating phase, and 14 (4.5%) in the terminal phase at the time of referral. The total score for symptom distress at the time of referral was the highest in the deteriorating phase (65.7), followed by the unstable (54.1), terminal (47.5), and stable phases (40.5). Furthermore, 20.4% of patients in the unstable phase at the time of referral moved to the stable phase after one week of the intervention. Conclusion This study identified the distribution and changes in the Phase of Illness of patients referred to palliative care teams. Assessments for the Phase of Illness must be standardized in palliative care teams to set benchmarks.

Cardiovascular magnetic resonance in muscular dystrophies: looking ahead.

Cardiac magnetic resonance (CMR) is an established tool for risk stratification in several cardiomyopathies, and its role in muscular dystrophies (MuD) looks promising. We sought to assess how CMR performs in predicting cardiac events in a real cohort of MuD patients. A prospective single-center study with the enrollment of consecutive adult MuD patients referred to cardiac screening from 2012 to 2018 with the collection of clinical and CMR data. During follow-up (FUP), major adverse cardiac events were considered a composite of device implantation, ventricular tachycardia (VT), hospitalization due to heart failure, and death. Sixty-five patients were included (mean age of 32±16, 51% female); the majority had myotonic dystrophy (34; 52.3%); most were asymptomatic (60; 92.3%) and at sinus rhythm (64; 98.5%). CMR was abnormal in 23 (43.3%) patients: left ventricle ejection fraction (LVEF) <55% was found in 7 patients, and late gadolinium enhancement (LGE) was present in 23 patients, mainly intra-myocardial or subepicardial (10 and 8 patients, respectively). During a median FUP of 77 months (interquartile range: 33), there were 7 deaths, 8 implanted devices, and one sustained VT. LVEF<55% and the presence of LGE were associated with the occurrence of all events (log rank test, p=0.002 and p=0.045, respectively). LVEF<55% was associated with a 6-fold higher risk of events (crude hazard ratio of 6.15; 95% confidence interval of 1.65-22.93), that remained significant after adjusting for LGE presence (adjusted hazard ratio of 4.81, 95% confidence interval of 1.07-15.9). In our cohort, CMR LVEF<55% and the presence of LGE were significantly associated with adverse events during follow-up, reinforcing the role of this technique on risk stratification of MuD populations.

MK-5684 (ODM-208), a CYP11A1 inhibitor, in patients with metastatic castration-resistant prostate cancer (mCRPC) with and without AR-LBD mutations: CYPIDES phase 2 results.

159 Background: MK-5684 (previously ODM-208) is a first-in-class, oral, non-steroidal, selective inhibitor of CYP11A1, the first and rate-limiting enzyme of steroid biosynthesis. MK-5684 suppresses the production of all steroid hormones and precursors that may activate the androgen receptor (AR) signaling pathway. Initial phase 1 (ASCO-GU 2022) and phase 2 results in AR-LBD mutation-positive (ESMO 2022) mCRPC patients were previously presented. Now we report phase 2 results for both AR-LBD mutation-positive and negative patients. Methods: MK-5684 5mg BID (with dexamethasone and fludrocortisone) was evaluated in an open-label expansion cohort in patients with progressing mCRPC who had previously received ≥1 line of 2nd generation AR pathway inhibitor and ≥1 line of taxane-based chemotherapy. An initial expansion cohort enrolled 45 patients with an activating AR-LBD mutation identified in cell-free DNA (Guardant360 assay, 74-gene panel), a subsequent extension cohort included mainly AR-LBD mutation-negative patients to attain comparable groups of about 60 patients each, with and without AR-LBD mutations. Study objectives were safety and preliminary efficacy assessed by PSA and RECIST response and standard safety measures. MK-5684 treatment was continued until subsequent disease progression. The study was conducted at 18 sites in France, Finland, UK and USA. Data are based on a 17 July 2023 data cut-off. Results: A total of 66 AR-LBD mutation-positive and 68 AR-LBD mutation-negative patients (median age 68.3 years) were enrolled and received MK-5684 treatment. 53% and 33.8% of patients had previously received both abiraterone and enzalutamide, and 63.6% and 55.9% patients had received cabazitaxel in AR-LBD mutation positive and negative groups respectively. MK-5684 profoundly suppressed androgen synthesis resulting in PSA50 responses in 55.6% and 16.7% of patients and PSA30 responses in 69.8% and 30.0% of patients, with and without AR-LBD mutations respectively. At the time of abstract data cut-off, objective responses by RECIST had occurred in 8 patients, all with AR-LBD mutations (ORR 20.5% for AR-LBD positive). MK-5684 was well-tolerated: the most common treatment-related adverse events were related to adrenal suppression with the rate of hospitalization for adrenal insufficiency being much lower than in phase 1 when typically higher MK-5684 doses were administered (3.0% vs. 33% respectively). Data with a minimum follow up of approximately 4 months after last patient enrolment will be presented. Conclusions: Administration of MK-5684 to heavily pre-treated mCRPC patients showed promising antitumor activity. PSA50 responses were most frequent among patients harboring activating AR-LBD mutations. Clinical trial information: NCT03436485 .