Failure Of Trials Research Articles

Can we predict trial failure among older adult-specific clinical trials using trial-level factors?

IntroductionConducting older adult-specific clinical trials can help overcome the lack of clinical evidence for older adults due to their underrepresentation in clinical trials. Understanding factors contributing to the successful completion of such trials can help trial sponsors and researchers prioritize studies and optimize study design. We aimed to develop a model that predicts trial failure among older adult-specific cancer clinical trials using trial-level factors. Materials and methodsWe identified phase 2–4 interventional cancer clinical trials that ended between 2008 and 2019 and had the minimum age limit of 60 years old or older using Aggregate Analysis of ClinicalTrials.gov data. We defined trial failure as closed early for reasons other than interim results or toxicity or completed with a sample of <85% of the targeted size. Candidate trial-level predictors were identified from a literature review. We evaluated eight types of machine learning algorithms to find the best model. Model fitting and testing were performed using 5-fold nested cross-validation. We evaluated the model performance using the area under receiver operating characteristic curve (AUROC). ResultsOf 209 older adult-specific clinical trials, 87 were failed trials per the definition of trial failure. The model with the highest AUROC in the validation set was the least absolute shrinkage and selection operator (AUROC in the test set = 0.70; 95% confidence interval [CI]: 0.53, 0.86). Trial-level factors included in the best model were the study sponsor, the number of participating centers, the number of modalities, the level of restriction on performance score, study location, the number of arms, life expectancy restriction, and the number of target size. Among these factors, the number of centers (odds ratio [OR] = 0.83, 95% CI: 0.71, 0.94), study being in non-US only vs. US only (OR = 0.32, 95% CI: 0.12, 0.82), and life expectancy restriction (OR = 2.17, 95% CI: 1.04, 4.73) were significantly associated with the trial failure. DiscussionWe identified trial-level factors predictive of trial failure among older adult-specific clinical trials and developed a prediction model that can help estimate the risk of failure before a study is conducted. The study findings could aid in the design and prioritization of future older adult-specific clinical trials.

Transfer or tailor? Implementing a technology‐supported intervention for noncommunicable diseases across contexts

Transfer or tailor? Implementing a technology‐supported intervention for noncommunicable diseases across contexts

Arthroscopic Management of the Hamate Proximal Pole Arthrosis.

In this retrospective study, all patients with arthrosis of the proximal pole of the hamate encountered in a 10-year period treated with arthroscopy were reviewed. Patient demographics, arthroscopic details, associated injuries, and procedures were reviewed. Functional and patient-reported clinical outcomes after arthroscopic osteochondroplasty were analyzed. An analysis of 39 patients who underwent arthroscopic osteochondroplasty showed a type II lunate prevalence of 87.2%. On wrist arthroscopy, a triangular fibrocartilaginous complex tear was the most common diagnosis (64.1%), followed by scapholunate ligament tear (61.5%) and lunotriquetral ligament tear (35.9%). All patients were managed arthroscopically with 100% procedural success. Average follow-up of 42.8 ± 37.7 months showed statistically significant improvements in the visual analog score and Mayo wrist score postoperatively (P < 0.01). Three patients (7.7%) failed the procedure at a mean of 23 ± 31.4 months. Risk factors for salvage operations were nondominant wrist involvement 100% (P = 0.04), lunotriquetral ligament injury 100% (P = 0.04), the absence of triangular fibrocartilaginous complex injury 100% (P = 0.04), and the presence of scapholunate advanced collapse 100% (P < 0.01). Wrist arthroscopy is valuable for accurately diagnosing and treating hamate arthrosis and identifying a wide variety of pathologies associated. This study showed arthroscopic osteochondroplasty produced satisfactory clinical results. Furthermore, the presence of scapholunate advanced collapse wrist offers its prognostic value in determining treatment failure.

The comparison of electroencephalography power and event related potential in success and failure during multitask game.

The first game-based treatment for children with attention-deficit hyperactivity disorder (ADHD) was approved by the United States Food and Drug Administration (FDA) in 2020. This game was developed for use at home as part of everyday training and can be used along with one's usual training plan. In this game, two tasks are performed in parallel: (1) a perceptual discrimination targeting task (response and not response and avoiding responding to sudden pop-up targets) and (2) a sensory-motor navigation task (players continuously adjust their location to interact with or avoid positional targets). However, the brain activity of people playing this game was not examined, and the immersive environment (3D virtual world) was not considered. Therefore, we aimed to develop a system to investigate brain activity using electroencephalography (EEG) during multitask gameplay in virtual reality (VR). In this experiment, we focused on the difference between the success and failure of the Go/No-Go task in a multitask game. We created a color discrimination task and a target tracking task in VR. The content of this game task was designed using previous multitask training. EEG and event data were recorded. Using event data, we can analyze the data in detail. We divided the trial types (Go and No-Go) and results (success and failure). We then compared the success and failure of each task. In the Go trial, the relative theta power in success at Fz was significantly higher than that of failure. However, no difference in power was observed in the No-Go trial. On the other hand, theta power was no different between success and failure in the other task. These results of the Go trial suggest that the participants were attentive to processing both tasks. Thus, it is possible that theta power in the frontal area 1 s before stimulation could predict the success or failure of the Go trial. On the other hand, the results of the No-Go trial may be due to the low number of No-Go failure trials and the fact that stimulus oversight is one of the factors for success.

Whole-brain microscopy reveals distinct temporal and spatial efficacy of anti-Aβ therapies.

Many efforts targeting amyloid-β (Aβ) plaques for the treatment of Alzheimer's Disease thus far have resulted in failures during clinical trials. Regional and temporal heterogeneity of efficacy and dependence on plaque maturity may have contributed to these disappointing outcomes. In this study, we mapped the regional and temporal specificity of various anti-Aβ treatments through high-resolution light-sheet imaging of electrophoretically cleared brains. We assessed the effect on amyloid plaque formation and growth in Thy1-APP/PS1 mice subjected to β-secretase inhibitors, polythiophenes, or anti-Aβ antibodies. Each treatment showed unique spatiotemporal Aβ clearance, with polythiophenes emerging as a potent anti-Aβ compound. Furthermore, aligning with a spatial-transcriptomic atlas revealed transcripts that correlate with the efficacy of each Aβ therapy. As observed in this study, there is a striking dependence of specific treatments on the location and maturity of Aβ plaques. This may also contribute to the clinical trial failures of Aβ-therapies, suggesting that combinatorial regimens may be significantly more effective in clearing amyloid deposition.

Fragment-based virtual screening identifies a first-in-class preclinical drug candidate for Huntington’s disease

Currently, there are no therapies available to modify the disease progression of Huntington’s disease (HD). Recent clinical trial failures of antisense oligonucleotide candidates in HD have demonstrated the need for new therapeutic approaches. Here, we developed a novel in-silico fragment scanning approach across the surface of mutant huntingtin (mHTT) polyQ and predicted four hit compounds. Two rounds of compound analoging using a strategy of testing structurally similar compounds in an affinity assay rapidly identified GLYN122. In vitro, GLYN122 directly binds and reduces mHTT and induces autophagy in neurons. In vivo, our results confirm that GLYN122 can reduce mHTT in the cortex and striatum of the R/2 mouse model of Huntington’s disease and subsequently improve motor symptoms. Thus, the in-vivo pharmacology profile of GLYN122 is a potential new preclinical candidate for the treatment of HD.

An Analysis of e-Iron: Updates from a Year of Experience with a Novel IV Iron Telemedicine Platform

Introduction: Intravenous iron (IVI) is increasingly being recognized as a safe and effective strategy in addressing the needs of patients with iron deficiency anemia (IDA) who fail to respond to oral iron, or are unable to tolerate it. However, convoluted referral processes frequently act as a barrier between referring providers and the infusion facility, resulting in significant underutilization of IVI. Capitalizing on a robust e-consult platform operational at our institution, e-IRON was built as a function in the EPIC EMR, to facilitate 'electronic’ referral for consideration for IVI, and in this way simplify and expedite the process of IVI referral. Using a template-based design, the e-IRON order 'gathers’ key information (indication, experience with oral iron, current lab-work), which, together with a 'chart-review', are evaluated by a specialist hematologist within 3 days. If IVI is deemed appropriate, this is scheduled directly. If a face-to-face hematology appointment is required, this is similarly scheduled. Where IVI is not deemed appropriate, guidance as to alternate management is provided. We previously demonstrated in a small cohort that e-IRON expedites hematologist assessment of patients’ candidacy for IVI, and significantly shortens the time from referral to infusion scheduling. Similarly, we demonstrated that only a small fraction of patients required in-person appointments. We now share our experience with a larger cohort, adding outcomes data, with an analysis of patient parameters observed in the year subsequent to e-IRON referral. Results: Over 1 year, 477 unique consults were placed. The overall rate of IVI approval was 65%, with similar results for each indication. The most common reason for denial (10.3%) was failure to document a failed trial of oral iron. In 8.4% IVI was denied because required information, typically current labwork, was not provided. Detailed chart review was performed on a sub-cohort of 119 (25%) patients, focusing on post e-IRON outcomes in an evaluation period of 1 year after the initial consult. In 76 patients (64%) IVI was approved, and of these 67 (88%) received at least their first dose, occurring a median of 12 days after the e-IRON consult was placed. In patients approved for IVI, and who received infusion, an average increase of 2.48 g/dL ((95% CI 2.48 - 3.20) was observed. Regardless of indication and intervention, patients had an average increase in Hb of 2.03 g/dL (95%CI 1.69-2.38) from their pre-consult value to their first post-consult value. All scheduled regimens comprised 1 or 2 infusions, using either iron dextran, or ferric carboxymaltose. The average dose was 1200 mgs, ranging from 750 to 2000 mgs. No adverse reactions to IVI were reported in this cohort. Of 15 patients in whom a trial of oral iron was recommended, 8 responded satisfactorily, 2 'failed’ their trial and subsequently received IVI, and in 5 follow-up was incomplete. Eight patients required blood transfusion during the evaluation period, most commonly in the context of peri-partum hemorrhage. In 19 patients, repeat e-IRON consults were placed during the evaluation period, and in 13 of these IVI was approved and administered, typically after information missing from the initial consult was provided. Follow up regarding patients’ anemia by the referring provider within 4 months of e-IRON occurred in 37 of 43 (86%) patients in whom IVI was not approved, and 63 of 76 (82%) in whom it was. Conclusions: Since the hematologist's involvement with the vast majority of e-IRON patients is limited to a brief chart review, concern had been expressed that this 'hands-off’ approach might result in suboptimal subsequent management and follow up. However this was not borne out in this outcome analysis, wherein we saw high rates of infusion completion in scheduled patients, and compliance with e-IRON recommendations on the part of referring providers. Our continued experience with e-iron verifies the feasibility and efficiency of a telemedicine approach in expediting the management of patients requiring IVI. In the vast majority of cases e-IRON enables unprecedentedly rapid determination of management and facilitation of IVI when appropriate, dispensing with the costly and time consuming traditional requirement of a face-to-face visit to the hematology clinic. The resultant benefits to patients, their primary care providers, and to over-burdened specialty providers are self-evident. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Not Everything is as it Seems: An Unusual Case of Pyelonephritis

Urinary tract infection is an important cause of hospitalization, morbidity and mortality, being responsible for an important fraction of health expenses. The main risk factors are urine flow obstruction, urinary catheters, immunosuppression and diabetes mellitus. We present a case of pyelonephritis that culminated in nephrectomy, finally unravelling an unexpected diagnosis. A 52-year-old male presented in the emergency department with two weeks of pain in the left iliac fossa that irradiated to the lumbar region and cloudy urine. Lab work revealed severe anaemia (4.9 g/dL), inflammatory markers elevation, leucoerythrocyturia, serum creatinine of 4.33 mg/dL and metabolic acidosis. Computed tomography scan showed a swollen left kidney with a staghorn calculus and intraparenchymal hypodensities. After a failed trial of large spectrum antibiotics, he was submitted to left radical nephrectomy with significant clinical improvement. Gross examination showed a markedly dilated pyelocalicial tree, filled with several staghorn calculi and purulent secretions with associated parenchymal atrophy. Histopathologic evaluation revealed exuberant chronic pyelonephritis with an acute inflammatory infiltrate that extended into the perinephric fat and multiple Schistosoma ova, predominantly calcified. The authors describe the case of a severe pyelonephritis with exuberant clinical and imagiological features and rare microbiological findings, suggesting previous genitourinary Schistosomiasis that predisposed to nephrolithiasis and chronic pyelonephritis.

Avoiding Clinical Trial Failures in Neglected Tropical Diseases: The Example of Chagas Disease.

Human clinical trials are expensive, and when they fail, they create the impression that a problem is intractable, thus depressing interest in future attempts. For neglected tropical diseases, where there are likely limited numbers of "shots on goal," such failures need to be assiduously avoided. Chagas disease drug discovery efforts have experienced more than its share of human clinical trial failures. Here are some guidelines, many specific for Chagas, but some that might also have application for other neglected tropical diseases. Chagas disease has major challenges (eg, the lack of a definitive test of cure) but also has outstanding advantages, among these the unmatched multi-species natural infection systems that can be exploited to de-risk compounds before human trials. Fully utilizing these advantages while frankly acknowledging and addressing the challenges should bring better options to patients, sooner.

Abstract 10209: The Effect of the Dual SGLT1 and 2 Inhibitor Sotagliflozin on Cardiovascular Mortality and Hospital Readmission Rates for Heart Failure at 30 and 90 Days Post Discharge in Patients With Type 2 Diabetes Hospitalized for Worsening Heart Failure in the SOLOIST-WHF Trial

Introduction: SGLT inhibitors demonstrate reductions in CV mortality and HHF in patients with diabetes and chronic HF. Despite therapy, patients hospitalized for worsening HF (WHF) are at high risk of death or readmission. Hypothesis: The SOLOIST-WHF trial admitted patients for their index WHF event and initiated randomized therapy during hospitalization. This study evaluated the effect of the SGLT1 and 2 inhibitor sotagliflozin on 30- and 90-day CV death and HF readmission rates after discharge. Methods: Of 1222 randomized patients with T2D, 86% were admitted for their index WHF event. Of them, 46% (n = 563) started study drug prior to or at discharge. In post hoc exploratory analyses, CV death and HF readmission (HHF or urgent visits for HF) rates were determined 30- or 90-days post discharge. Comparisons were done by Cochran-Mantel-Haenszel test stratified by region and baseline LVEF (&lt;50%, ≥50%). Results: Treatment with sotagliflozin showed significant relative risk reduction of &gt;50% for readmission for non-fatal HF-related events or the composite of CV death and readmission for HF-related events within 30 or 90 days of discharge vs placebo (Table 1). The sotagliflozin safety profile in those windows was generally consistent with the overall study duration. Incidence of adverse events (AEs) and serious AEs was similar between groups. Increased incidence of diarrhea and volume-related AEs was noted with sotagliflozin. No appreciable eGFR change from baseline occurred at 30 days, but there was lower incidence of AEs linked to acute kidney injury with sotagliflozin. Conclusions: Sotagliflozin, given to patients with T2D prior to or at hospital discharge after an episode of WHF, was well tolerated and resulted in a significant &gt;50% reduction in CV mortality or readmission for a HF event at 30 and 90 days post-discharge.

Abstract 100: Multi-drug Cocktail Approach After Asphyxial Cardiac Arrest And Cardiopulmonary Bypass Resuscitation In Rats

Background: Cardiac arrest (CA) is a leading cause of death in the US. There are limited therapies that substantially improve survival with good neurologic outcomes. The lack of neuroprotective drugs has been cited as a major roadblock to improved outcomes. There have been many failed human trials of potentially neuroprotective drugs. However, most of the failed prior studies have focused on a single drug or single pathological pathway. By contrast, our metabolomic data suggests that after CA multiple pathways are severely dysregulated. Objective: The aim of this study was to develop and test the therapeutic effectiveness of a multi-drug cocktail targeting multiple dysfunctional pathways observed during brain ischemia-reperfusion. We sought to increase survival with good neurological outcomes in a highly lethal rat model of 20 min CA followed by cardiopulmonary bypass (CPB) resuscitation. Methods: A multi-drug cocktail formulation was developed comprised of ten drugs (Metformin, poloxamer 188, N- acetylcysteine, Sulbutiamine, Zoniporide, SS-31, Cyclosporin A, CoQ10, Vitamin C, and Edaravone) focusing on distinct metabolic pathways of ischemia-reperfusion injury. Male Sprague-Dawley rats (400-500 g) underwent 20 min of asphyxial-CA and 30 min of CPB resuscitation. After the resumption of spontaneous circulation (ROSC), rats received either cocktail or a vehicle (n=6) through a femoral vein for over a 20-minute. Animals were extubated after 4 h of mechanical ventilation. Body temperature was maintained at 37.0 ± 0.5°C. Outcomes assessed include a 4 h survival time and retention of corneal reflex. Results: Cocktail treatment resulted in 4/6 rats surpassing the 4 h survival window, while only 2/6 rats after vehicle treatment. The median survival time was 240.53 min vs 120.62 min for a cocktail vs vehicle, respectively (p=0.067). Furthermore, 4/6 rats treatment with a cocktail demonstrated retention of corneal reflex after 4 h compared with 2/6 rats after vehicle treatment. Conclusion: This pilot study is the first to use a multi-drug cocktail in a severe CA rodent model that demonstrates a trend for better survival and corneal reflex retention. Future studies of cocktails seem warranted if neuroprotective therapies are contemplated in the setting of CA.

Helper innate lymphoid cells as cell therapy for cancer.

Although the first cancer immunotherapy was given in the clinic more than a century ago, this line of treatment has remained more of a distant goal than a practical therapy due to limited understanding of the tumour microenvironment and the mechanisms at play within it, which led to failures of numerous clinical trials. However, in the last two decades, the immune checkpoint inhibitors (ICIs) and chimeric antigen receptor-T cell therapies have revolutionized the treatment of cancer and provided proof-of-concept that immunotherapies are a viable option. So far, immunotherapies have majoritarily focused on utilizing T cells; however, T cells are not autonomous but rather function as part of, and therefore are influenced by, a vast cast of other immune cells, including innate lymphoid cells (ILCs). Here, we summarize the role of ILCs, especially helper ILCs, in tumour development, progression and metastasis, as well as their potential to be used as immunotherapy for cancer. By reviewing the studies that used helper ILCs as adoptive cell therapy (ACT), we highlight the rationale behind considering these cells as novel ACT for cancer as well as identify open questions and areas for future research.

CO delivery nanosystem based on regenerative bioactive zinc MOFs highlights intercellular crosstalk for enhanced vascular remodeling in CLI therapy

Therapeutic angiogenesis is a promising approach for the treatment of critical limb ischemia (CLI), but always face failure in clinical trials. The existing strategies primarily regulate a population of independent cells and ignore intercellular crosstalk, which may constrain efficacy. Inspired by the “self-healing” of organisms, we proposed a novel concept of “biomimetic dual cellular co-regulation”, i.e., regulating both vascular endothelial cells (VECs) or macrophages (Mφs), the protagonists in ischemic repair, and highlighting intercellular crosstalk to break the efficiency bottleneck of conventional strategies. Herein, bioactive zinc metal–organic frameworks (Zn-MOFs)-based carbon monoxide (CO) delivery nanoparticles coated with hyaluronic acid (HA)-CAG peptide (denoted as HA-CAG@ZIF8@CO) were developed, which can simultaneously target and regulate VECs and Mφs and enhance their interactions, with a view to amplify the synergistic cooperation in vascular remodeling. HA-CAG@ZIF8@CO promoted VECs morphogenesis through zinc ion and CO release, normalized microenvironment, and induced Mφ polarization to pro-healing M2-type, which further amplified angiogenesis through the secretion of pro-angiogenic cytokines. Excitingly, the intrinsic communication between VECs and M2-type Mφs enabled the significant enhancement of angiogenic activity. In summary, the dual cellular co-regulatory nanomedicine HA-CAG@ZIF8@CO modulates the intercellular crosstalk and represents a new possibility for therapeutic angiogenesis with clinical implications for ischemic repair.

S1400 The Complexity of NASH Cirrhosis Clinical Trials: Screen Failure Reasons and Baseline Patient Characteristics

Introduction: Patients with NASH cirrhosis has the highest likelihood of developing major adverse liver related events and an unmet need in terms of therapeutic options. Several drugs are being tested in patients with NASH cirrhosis in phase 2 trials. Screen failure (SF) reasons in non-cirrhotic NASH trials have been described; however, limited data exists on the reason for screen failure reasons in NASH cirrhosis trials. The aim of this study was to understand the reasons for screen failure in 5 NASH cirrhosis trials and to describe the patient's characteristics of both screens failed subjects and those who randomised. Methods: Data on patients who were presented for screening visits for five phase 2 NASH cirrhosis trials at one research site were analysed. The reasons for screen failure were divided into 4 major categories: 1. Biopsy, 2. Laboratory tests, 3. Imaging tests, 4. Other. Baseline characteristics including demographics, clinical history, lab values, findings from imaging tests and biopsy were collected. Characteristics of patients that screen failed were compared to those who randomised using 2-sided t-test, p value < 0.05 was considered statistically significant. Results: 68 patients were included in the analysis. 23 randomised (33.8%) and 45 screen failed (66.17%). The mean age was 57.98 years with 45% (31) of the population being male. Mean BMI in the whole population was 38.38 Kg/m2. 51.47% (35) of the patients were found to have type 2 diabetes. The reasons for screen failure were as follows: 4 (8.8%) on biopsy, 12 (26.6%) on labs, 11 (24.4%) in imaging tests, 15 (33.3%) for other reasons. The top 4 causes included in the other category were patients outside of the screening window, using prohibited medications, subject dropping out and presence of esophageal varices. There was no significant difference between the screen failure group and the randomised group in terms of platelet count, INR, bilirubin, FIB4 score and AGILE4 score (p > 0.05 for all). (Figure) Conclusion: NASH cirrhosis trials have similar screen failure rates compared to non-cirrhotic trials; however, the reasons for screen failure are different. In NASH cirrhosis trials, fewer patients screen failed because of not meeting histologic criteria on liver biopsy which has been the major reason for screen failure in non-cirrhotic trials. Baseline laboratory and imaging tests were not different between patients who screen failed and those who randomised. (Table)Figure 1.: Minor causes of screen failure Table 1. - Comparison chart showing basic characteristics of randomised and screen failure population 2 sided T Test Mean Mean Mean Total Population Randomised population Screen Failure population T-Test Age 58.31 60.95 56.88 BMI 37.38 39.88 37.05 Hba1C 6.42 6.43 6.46 % Diabetes 52.90% 48.50% 51.40% Platelets 177.23 159.26 187.30 0.13 Bilirubin 0.795 0.83 0.76 0.52 INR 1.13 1.15 1.12 0.24 kPa 23.31 24.03 22.24 0.79 Agile 4 0.44 0.518 0.42 0.23 CAP score 302.35 310.33 297.57 0.59 Fib 4 3.12 2.95 3.41 0.53

Dementia Prevention in Clinical Practice.

Over 55 million people globally are living with dementia and, by 2050, this number is projected to increase to 131 million. This poses immeasurable challenges for patients and their families and a significant threat to domestic and global economies. Given this public health crisis and disappointing results from disease-modifying trials, there has been a recent shift in focus toward primary and secondary prevention strategies. Approximately 40% of Alzheimer's disease (AD) cases, which is the most common form of dementia, may be prevented or at least delayed. Success of risk reduction studies through addressing modifiable risk factors, in addition to the failure of most drug trials, lends support for personalized multidomain interventions rather than a "one-size-fits-all" approach. Evolving evidence supports early intervention in at-risk patients using individualized interventions directed at modifiable risk factors. Comprehensive risk stratification can be informed by emerging principals of precision medicine, and include expanded clinical and family history, anthropometric measurements, blood biomarkers, neurocognitive evaluation, and genetic information. Risk stratification is key in differentiating subtypes of dementia and identifies targetable areas for intervention. This article reviews a clinical approach toward dementia risk stratification and evidence-based prevention strategies, with a primary focus on AD.

EFFECT OF MODAFINIL ON TIME TO WEAN FROM MECHANICAL VENTILATION

SESSION TITLE: Late Breaking Posters in Critical CareSESSION TYPE: Original Investigation PostersPRESENTED ON: 10/18/2022 01:30 pm - 02:30 pmPURPOSE: Modafinil is a wake promoting agent commonly used in sleep disorders. Sedation during mechanical ventilation in the ICU disrupts circadian rhythms and results in sleep disturbances and delirium. Wakefulness and ability to follow commands is a key component of successful extubation. This study evaluates the effect of modafinil on time to wean from mechanical intubation.METHODS: This study was a retrospective study conducted at a single urban center. Chart review was performed on 511 patients. Exclusion criteria included patients who expired, were transferred to hospice for terminal extubation or those who required tracheostomy (n=256). Sub-group analysis was done on patients intubated at least 5 days prior to initiation of weaning trials (n=81). Data was analyzed with medcalc statistical software.RESULTS: Patients who were treated with Modafinil had an overall longer time to wean from the ventilator as compared to patients who were not treated with Modafinil. Further evaluation showed patients who received Modafinil were intubated at least 5 days or more prior to initiation of the weaning process. Sub-group analysis of these patients intubated at least 5 days or more showed a decrease in mean time to wean from ventilation by 1 day (4 days with Modafinil and 5 days without Modafinil) with findings not statistically significant (p=0.673).CONCLUSIONS: Although our study showed reduction in mean number of days to wean from ventilation with Modafinil, these results were not statistically significant due to reduction in the power of the study after further exclusion of patients intubated less than 5 days during sub-group analysis. Future studies should involve a higher number of patients for increased power and assess other variables such as dosage effect of Modafinil, RASS score, GCS score, presence of other sedating medications, and reason for failure of pressure support trial.CLINICAL IMPLICATIONS: This research may serve as the basis for future studies regarding the effect of Modafinil on time to wean from ventilation. Implications include potentially decreasing time to wean from the ventilator and may serve as a strategy to decrease total time of intubation in patients by promoting wakefullness and restoring circadian rhythms. Decreasing time of intubation is beneficial to shorten ICU stay and minimize risks associated with prolonged mechanical ventilation.DISCLOSURES:No relevant relationships by AdeYinka AdeniyiNo relevant relationships by Chelsae Keeney SESSION TITLE: Late Breaking Posters in Critical Care SESSION TYPE: Original Investigation Posters PRESENTED ON: 10/18/2022 01:30 pm - 02:30 pm PURPOSE: Modafinil is a wake promoting agent commonly used in sleep disorders. Sedation during mechanical ventilation in the ICU disrupts circadian rhythms and results in sleep disturbances and delirium. Wakefulness and ability to follow commands is a key component of successful extubation. This study evaluates the effect of modafinil on time to wean from mechanical intubation. METHODS: This study was a retrospective study conducted at a single urban center. Chart review was performed on 511 patients. Exclusion criteria included patients who expired, were transferred to hospice for terminal extubation or those who required tracheostomy (n=256). Sub-group analysis was done on patients intubated at least 5 days prior to initiation of weaning trials (n=81). Data was analyzed with medcalc statistical software. RESULTS: Patients who were treated with Modafinil had an overall longer time to wean from the ventilator as compared to patients who were not treated with Modafinil. Further evaluation showed patients who received Modafinil were intubated at least 5 days or more prior to initiation of the weaning process. Sub-group analysis of these patients intubated at least 5 days or more showed a decrease in mean time to wean from ventilation by 1 day (4 days with Modafinil and 5 days without Modafinil) with findings not statistically significant (p=0.673). CONCLUSIONS: Although our study showed reduction in mean number of days to wean from ventilation with Modafinil, these results were not statistically significant due to reduction in the power of the study after further exclusion of patients intubated less than 5 days during sub-group analysis. Future studies should involve a higher number of patients for increased power and assess other variables such as dosage effect of Modafinil, RASS score, GCS score, presence of other sedating medications, and reason for failure of pressure support trial. CLINICAL IMPLICATIONS: This research may serve as the basis for future studies regarding the effect of Modafinil on time to wean from ventilation. Implications include potentially decreasing time to wean from the ventilator and may serve as a strategy to decrease total time of intubation in patients by promoting wakefullness and restoring circadian rhythms. Decreasing time of intubation is beneficial to shorten ICU stay and minimize risks associated with prolonged mechanical ventilation. DISCLOSURES: No relevant relationships by AdeYinka Adeniyi No relevant relationships by Chelsae Keeney

Tribulations of conducting critically ill cancer patients research: Lessons from a failed septic shock trial and Murphy's law

Tribulations of conducting critically ill cancer patients research: Lessons from a failed septic shock trial and Murphy's law

Deciphering the Clinical Trials of Immunotherapy in Glioblastoma: What a Neuroradiologist Needs to Know

Glioblastoma is the most common malignant adult primary intracranial neoplasm. Although a multidisciplinary approach combining surgical resection followed by radiation therapy and chemotherapy is currently applied to the target glioblastoma, prognosis and survival outcomes are poor. Consequently, a range of immunotherapeutic approaches is being actively investigated to address the need for more efficacious glioblastoma treatments. Given the rapid growth of immunotherapy in the treatment of glioblastoma, neuroradiologists need to be familiar with the basic concepts and mechanisms of immunotherapy, along with the current state and future directions in this field. In the present study, we review different types of immunotherapies, including immune checkpoint inhibitors and glioblastoma vaccines, as well as their application to the treatment of glioblastoma. Moreover, we review clinical trials of immunotherapy in glioblastoma, discuss reasons for trial failure, and summarize future directions for research.Learning Objective: To describe the different types of immunotherapies and their application to the treatment of glioblastoma and explain the results of associated clinical trials along with reasons for trial failure and future directions

How can secondary dementia prevention trials of Alzheimer's disease be clinically meaningful?

After clinical trial failures in symptomatic Alzheimer's disease (AD), our field has moved to earlier intervention in cognitively normal individuals with biomarker evidence of AD. This offers potential for dementia prevention, but mainly low and variable rates of progression to AD dementia reduce the usefulness of trials' data in decision making by potential prescribers. With results from several Phase 3 secondary prevention studies anticipated within the next few years and the Food and Drug Administration's recent endorsement of amyloid beta as a surrogate outcome biomarker for AD clinical trials, it is time to question the clinical significance of changes in biomarkers, adequacy of current trial durations, and criteria for treatment success if cognitively unimpaired patients and their doctors are to meaningfully evaluate the potential value of new agents. We argue for a change of direction toward trial designs that can unambiguously inform clinical decision making about dementia risk and progression.

Risk Factors and Real-World Short-Term Outcomes of a Failed Trial of Void After Rezum Therapy in a Multiethnic Population.

Background: Postoperative urinary retention is a common complication following surgery for benign prostatic hyperplasia. We aimed to identify risk factors for a failed trial of void (TOV) following treatment with the Rezum system and assess the impact of a failed TOV on short-term outcomes. Methods: A single-office retrospective study was conducted on patients treated with Rezum therapy between 2017 and 2019. A urinary catheter was placed in all patients following Rezum therapy. Demographic data and outcome measures, including the International Prostate Symptom Score (IPSS), quality of life (QoL), maximum urinary flow rate (Qmax), postvoid residual (PVR), and adverse events, were analyzed at baseline and 1, 3, and/or 6 months postoperatively. Risk factors were identified through multivariate logistic regression analysis. Results: A total of 289 patients were included. Thirty-five patients (12.1%) failed a TOV, while 254 (87.9%) had an effective TOV. All patients were given a TOV after a median of 5 days (4-5). Those who failed the TOV spent an additional mean of 13.7 ± 13.3 days with a catheter. Patients who failed the TOV were more likely to get a urinary tract infection compared with those who had an effective TOV (20.0% vs 4.7%, p < 0.001). All patients experienced significant improvements in IPSS, QoL, and Qmax at 1, 3, and/or 6 months. On multivariate analysis, a high baseline PVR was the only independent predictor of a failed TOV (odds ratio: 1.01, 95% confidence interval 1.00-1.01). A greater proportion of patients with a baseline PVR >200 mL failed the TOV (40.0%) compared with patients with a baseline PVR <200 mL (10.9%, p = 0.008). Conclusions: Approximately one in eight patients failed the TOV following Rezum therapy. Baseline PVR was the only independent risk factor for a failed TOV. Nevertheless, all patients experienced significant relief of urinary symptoms. Patients with high baseline PVR, particularly >200 mL, may require a catheter for an extended duration.