Independent Adjudication Committee Research Articles

Abstract PO3-17-07: Real-world experience with trastuzumab deruxtecan in patients with breast cancer: 6 month-interim analysis of an all-patient postmarketing surveillance in Japan

Abstract Background: Trastuzumab deruxtecan (T-DXd) is an anti-human epidermal growth factor receptor 2 (HER2) antibody-drug conjugate. T-DXd has shown great efficacy in HER2-positive breast cancer, hence receiving approval in Japan in March 2020. In Japan, all-patient postmarketing surveillance (PMS) is underway to evaluate the risk of interstitial lung disease/pneumonitis (ILD/p) in patients with breast cancer treated with T-DXd. Due to the limited generalizability of results from clinical trials, there is a need for more information about ILD/p in a real-world setting. Herein we present an interim analysis of the large-scale all-patient PMS. Methods: This is an observational, multicenter, all-patient PMS (jRCT1080225197) with an observation period of 18 months that enrolled all patients treated with T-DXd for recurrent/advanced HER2-positive breast cancer. Patients who initiated T-DXd treatment between May 2020 (launch date of T-DXd) and May 2021 were included in the interim analysis to ensure the observation period of 6 months from the initial treatment of T-DXd. This interim analysis is based on safety data from the first 6 months of 1204 patients. Data collected includes baseline characteristics and information on ILD/p. All potential ILD/p (identified based on the AE terms) reported by physicians were adjudicated by an independent ILD adjudication committee. The incidence of ILD/p was calculated from adjudicated drug-related ILD/p. Results: The interim analysis set included 1204 patients with median age of 60 years. Three of the 1204 patients (0.2%) received T-DXd as a first-line treatment, 30 (2.5%) as second-line, 1159 (96.3%) as third- line or later treatment. At baseline, 105 (8.7%) of patients had an Eastern Cooperative Oncology Group performance status (ECOG PS) 2 or greater, 8 (0.7%) had severe renal impairment (15≤ creatinine clearance (CLcr) < 30 mL/min), 4 (0.3%) had end-stage renal disease (CLcr < 15 mL/min), 5 (0.4%) had severe liver impairment (total bilirubin >4.5 mg/dL), and 32 (2.7%) had comorbid ILD/radiation pneumonitis. Those were defined as exclusion criteria in clinical trials of T-DXd. The median dose at the start of administration of T-DXd was 5.4 mg/kg (range:2.7-5.4). During the first 6 months from the initial treatment, T-DXd was discontinued in 403 (33.5%) of the 1204 patients. The most common reasons for discontinuation were disease progression in 232 (57.6%) of the discontinued 403 patients followed by ILD/p in 97 (24.1%) of the 403 patients. In the first 6 months, the incidence of all grade, grade ≥3, and grade 5 ILD/p were 8.2% (n=99), 1.7% (n=20) and 0.4% (n=5), respectively. The incidence of ILD/p stratified by baseline characteristics identified as potential risk factors of drug-related ILD/p is shown in Table. Conclusion: This is the first report demonstrating real-world experience with T-DXd in Japan. The interim analysis revealed useful information including patient and treatment profiles of T-DXd and the incidence of ILD/p during the first 6 months from the initial treatment in a real-world setting in Japan. The final analysis of the ongoing PMS is warranted for further evaluation. Incidence of interstitial lung disease/pneumonitis by patient baseline characteristics XX XX ILD/p: interstitial lung disease/pneumonitis, 95% CI: 95% confidence interval, CLCr: creatinine clearance using the Cockcroft-Gault equation * includes ILD/p, pulmonary fibrosis, radiation pneumonitis, chronic obstructive pulmonary disease, emphysema, and Asthma (Source: Powell CA, Modi S, Iwata H, et al. Pooled analysis of drug-related interstitial lung disease and/or pneumonitis in nine trastuzumab deruxtecan monotherapy studies. ESMO Open 2022;7(4):100554) Citation Format: Junji Tsurutani, Hideki Mizutani, Ayumi Tanabe. Real-world experience with trastuzumab deruxtecan in patients with breast cancer: 6 month-interim analysis of an all-patient postmarketing surveillance in Japan [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-17-07.

Swissped-RECOVERY: masked independent adjudication for the interpretation of non-randomised treatment in a two-arm open-label randomised controlled trial (methylprednisolone vs immunoglobulins) in Paediatric Inflammatory Multisystem Syndrome Temporally Associated with SARS-CoV-2 (PIMS-TS) involving 10 secondary and tertiary paediatric hospitals in Switzerland

ObjectivesIn trials of acute severe infections or inflammations frequent administration of non-randomised treatment (ie, intercurrent event) in response to clinical events is expected. These events may affect the interpretation of...

Letermovir safety and efficacy for cytomegalovirus prophylaxis in adult Japanese kidney transplant recipients: a multicenter, open-label, noncomparative Phase 3 study.

Letermovir is approved for cytomegalovirus (CMV) prophylaxis in adult allogeneic hematopoietic cell transplantation recipients worldwide and is also approved in the United States for CMV prophylaxis in adult high-risk (D+/R-) kidney transplant recipients (KTRs). The safety and efficacy of letermovir for CMV prophylaxis in adult Japanese KTRs are reported here. In this Phase 3, single-arm, open-label study, adult Japanese KTRs with CMV serostatuses D+/R-, D+/R+, and D-/R+ received letermovir 480mg daily orally within 7days post-transplant through Week 28. Participants were followed through Week 52. The primary objective was to evaluate letermovir safety and tolerability. Efficacy was a secondary objective, measured by CMV disease, CMV disease or infection requiring intervention, and quantifiable CMV DNAemia. All CMV disease cases were confirmed by an independent adjudication committee. Among 22 participants (12 were D+/R-) who received letermovir prophylaxis, 20 (90.9%) experienced ≥ 1 AE through Week 28. Most AEs were mild to moderate in severity; no deaths were reported. During the prophylaxis period through Week 28, one transient case of quantifiable CMV DNAemia was detected, but no CMV disease or infection requiring intervention was reported. Through Week 52, four D+/R- participants met the endpoint of CMV disease or infection requiring intervention, of whom two had committee-confirmed CMV syndrome; all recovered with CMV therapy. A total of 5 participants had quantifiable CMV DNAemia through Week 52. Letermovir was generally well tolerated, and the data support its use for the prevention of CMV disease/infection in adult Japanese KTRs. ClinicalTrials.gov NCT04129398.

Mental health outcomes in patients with moderate to severe psoriasis treated with bimekizumab: Analysis of phase 2/3 randomized trials

Patients with psoriasis have increased risk of suicidal ideation and behavior (SIB) and depression. Bimekizumab, a biologic that inhibits interleukin (IL)-17A and IL-17F, received Food and Drug Administration approval in 2023 for moderate to severe plaque psoriasis, following 2021 European Medicines Agency approval. To report SIB and depression in patients with moderate to severe psoriasis treated in bimekizumab clinical trials. Mental health changes, including neuropsychiatric events, were actively monitored across 9 bimekizumab clinical trials in psoriasis phase 2/3 trials. The patient-reported electronic Columbia-Suicide Severity Rating Scale (measuring SIB) and Patient Health Questionnaire-9 (measuring depression) were administered, monitored by an independent Neuropsychiatric Adjudication Committee. Throughout 7166 patient-years (PY) of bimekizumab exposure, the adjudicated SIB rate was 0.13/100PY; SIB ranges for the general psoriasis population and patients receiving anti-IL-17A/anti-IL-23 therapies are 0.09 to 0.54/100PY and 0.09 to 0.19/100PY, respectively. At week 16, 92.9% vs 81.1% of bimekizumab- vs placebo-treated patients had no/minimal depression. Newonset positive electronic Columbia-Suicide Severity Rating Scale responses and mean Patient Health Questionnaire-9 scores were low for bimekizumab-treated patients. Patient exclusion for significant/severe prespecified SIB/depression history. The long-term adjudicated SIB rate with bimekizumab was low and within ranges reported in the general psoriasis patient population and psoriasis patients treated with anti-IL-17A/anti-IL-23 biologics. Screening/monitoring questionnaires reported low SIB and depression levels.

Ultrashort VIBE-Dixon versus Cine and late gadolinium enhancement MRI sequences for cardiac thrombus detection

PurposeTo determine the diagnostic accuracy of volumetric interpolated breath-hold examination sequences with fat suppression in Dixon technique (VIBE-Dixon) for cardiac thrombus detection. MethodFrom our clinical database, we retrospectively identified consecutive patients between 2014 and 2022 who had definite diagnosis or exclusion of cardiac thrombus confirmed by an independent adjudication committee, serving as the reference standard. All patients received 2D-Cine plus 2D-Late-Gadolinium-Enhancement (Cine + LGE) and VIBE-Dixon sequences. Two blinded readers assessed all images for the presence of cardiac thrombus. The diagnostic accuracy of Cine + LGE and VIBE-Dixon was determined and compared. ResultsAmong 141 MRI studies (116 male, mean age: 61 years) mean image examination time was 28.8 ± 3.1 s for VIBE-Dixon and 23.3 ± 2.5 min for Cine + LGE. Cardiac thrombus was present in 49 patients (prevalence: 35 %). For both readers sensitivity for thrombus detection was significantly higher in VIBE-Dixon compared with Cine + LGE (Reader 1: 96 % vs.73 %, Reader 2: 96 % vs. 78 %, p < 0.01 for both readers), whereas specificity did not differ significantly (Reader 1: 96 % vs. 98 %, Reader 2: 92 % vs. 93 %, p > 0.1). Overall diagnostic accuracy of VIBE-Dixon was higher than for Cine + LGE (95 % vs. 89 %, p = 0.02) and was non-inferior to the reference standard (Delta ≤ 5 % with probability > 95 %). ConclusionsBiplanar VIBE-Dixon sequences, acquired within a few seconds, provided a very high diagnostic accuracy for cardiac thrombus detection. They could be used as stand-alone sequences to rapidly screen for cardiac thrombus in patients not amenable to lengthy acquisition times.

Real-world experience with trastuzumab deruxtecan among patients with gastric cancer: 4 month-interim analysis of an all-patient post-marketing surveillance study in Japan.

273 Background: Interstitial lung disease (ILD) is an important identified risk in the Japanese risk management plan of trastuzumab deruxtecan (T-DXd). In Japan, all-patient post-marketing surveillance (PMS) is underway to investigate the risk of ILD among patients with gastric cancer treated with T-DXd in a real-world setting. We present an interim analysis of the large-scale all-patient PMS. Methods: This is an observational, multicenter, all-patient PMS (jRCT2001200001) with an observation period of 12 months that enrolled all patients treated with T-DXd for HER2-positive unresectable advanced or recurrent gastric cancer between Sep 2020 and Dec 2021. This interim analysis is based on safety data from the first 4 months of all enrolled patients. All potential ILD (identified based on the pre-specified list of AE terms) reported by physicians were adjudicated by an independent ILD adjudication committee (ILD-AC). The incidence of ILD was calculated from adjudicated drug-related ILD. Results: The interim analysis set included 1074 patients with median age of 70 years (range: 23-100). Of the 1074 patients, 1051 (97.9%) received T-DXd as third-line or later treatment. One hundred and eight patients (10.1%) had an Eastern Cooperative Oncology Group performance status (ECOG PS) 2 or greater, and 32 (3.0%), 3 (0.3%), and 23 (2.1%) patients had severe renal impairment (15≤ creatinine clearance (CL) &lt;30 mL/min), end-stage renal disease (CL &lt;15 mL/min), and ILD/radiation pneumonitis at baseline, respectively (all of which were defined as exclusion criteria in clinical trials of T-DXd). Median initial dose of T-DXd was 6.4 mg/kg (range: 3.1-6.4). Median treatment duration of T-DXd was 4.0 months (range: 0.7-4.0). During the first 4 months from the initial treatment, T-DXd was discontinued in 50.9% (547/1074) of patients. The most common reasons for treatment discontinuation were disease progression (n=390, 71.3%), adverse events other than ILD (n=76, 13.9%), and ILD (n=56, 10.2%). All potential ILD that occurred during the first 4 months were adjudicated by ILD-AC, and the incidence of all grades, grade ≥3, and grade 5 adjudicated drug-related ILD were 5.2% (n=56), 1.5% (n=16) and 0.7% (n=7), respectively. Of the 56 patients with adjudicated drug-related ILD, 54 (96.4%) discontinued T-DXd. The incidence of adjudicated drug-related ILD by time from initial treatment of T-DXd were 0.7% (7/1074) at ≤ 1 month, 2.0% (19/949) at 1-2 months, 2.7% (22/829) at 2-3 months, and 1.2% (8/652) at 3-4 months. Conclusions: The interim analysis revealed patient experiences and treatment profiles of T-DXd and the incidence of ILD during the first 4 months since initial treatment in a real-world setting in Japan. The final analysis including a risk factor analysis for ILD of the ongoing PMS is planned.

Diagnostic Accuracy of Contrast-Enhanced Thoracic Photon-Counting Computed Tomography for Opportunistic Locoregional Staging of Breast Cancer Compared With Digital Mammography: A Prospective Trial.

Accurate locoregional staging is crucial for effective breast cancer treatment. Photon-counting computed tomography (PC-CT) is an emerging technology with high spatial resolution and the ability to depict uptake of contrast agents in tissues, making it a promising tool for breast cancer imaging. The aim of this study was to establish the feasibility of locoregional staging of breast cancer through contrast-enhanced thoracic PC-CT, assess its diagnostic performance, and compare it with that of digital mammography (DM). Patients with newly diagnosed breast cancer, DM, and indication of thoracic CT staging were prospectively enrolled in this clinical cohort study over a period of 6 months. Participants underwent contrast-enhanced thoracic PC-CT and breast magnetic resonance imaging in prone position. After blinding to patient data, 2 radiologists independently rated PC-CT and DM regarding the following 6 characteristics: (1) diameter of the largest mass lesion, (2) infiltration of cutis/pectoral muscle/thoracic wall, (3) number of mass lesions, (4) presence/absence of adjacent ductal carcinoma in situ (DCIS), (5) tumor conspicuity, and (6) diagnostic confidence. Reference standard was generated from consensus reading of magnetic resonance imaging combined with all histopathological/clinical data by an independent adjudication committee applying TNM eighth edition. Among 32 enrolled female subjects (mean ± SD age, 59 ± 13.0 years), diagnostic accuracy for T-classification was higher for PC-CT compared with DM (0.94 vs 0.50, P < 0.01). Moreover, the correlation of the number of detected tumor masses with the reference standard was stronger for PC-CT than for DM (0.72 vs 0.50, P < 0.01). We observed that PC-CT significantly (P < 0.04) outperformed DM regarding not only sensitivity (0.83 and 0.25, respectively) but also specificity (0.99 and 0.80, respectively) for adjacent DCIS. The κ values for interreader reliability were higher for PC-CT compared with DM (mean 0.88 vs 0.54, respectively; P = 0.01). Photon-counting computed tomography outperformed DM in T-classification and provided higher diagnostic accuracy for the detection of adjacent DCIS. Therefore, opportunistic locoregional staging of breast cancer in contrast-enhanced thoracic PC-CT is feasible and could overcome limitations of DM with the potential to improve patient management.

Predicting Major Bleeding in Patients with Venous Thromboembolism on Extended Anticoagulation Therapy Using Follow-up Data and Long Short-Term Memory Based Recurrent Neural Network

Background: It is often challenging for physicians to decide on the duration of anticoagulation treatment for patients with venous thromboembolism (VTE), as they need to weigh the risk of recurrent thrombosis and bleeding at the same time. Several clinical models have been developed to help physicians identify patients with high risk of bleeding. However, these tools use only the baseline clinical information and are not able to incorporate the clinical conditions and events that occur over time that may influence the risk of bleeding. Therefore, capturing the patterns and relationships in the continuously changing time series of clinical data could be a more powerful approach to developing predictor models than just relying on the baseline clinical information. Nonetheless, creating predictive models from follow-up clinical information is challenging given that time series clinical data are non-uniform, high-dimensional, multivariate observations. Here, we present the first attempt at creating a model that uses the time series follow-up information to predict major bleeding over time using a Recurrent Neural Network (RNN) with Long Short-Term Memory (LSTM) cells. Methods: 2542 patients diagnosed with VTE were enrolled in a prospective cohort study over 8 years. In addition to recording their clinical information at baseline, 6-month follow-up interviews were conducted using a standard script to monitor bleeding status and record clinical information. Major bleeding was defined by the International Society on Thrombosis and Haemostasis, with suspected bleeding events classified by an independent adjudication committee. Overall, 118 patients had major bleeding - a 4.6% incidence rate. The median and mode of the clinical variables were used to impute missing numerical and categorical values, respectively, and for patients who had no follow-up information, for whom bleeding occurred before the first follow-up, an artificial follow-up data point was generated from their corresponding baseline data. Thereafter, the data was divided into two stratified sets: 70% for training, and 30% for testing. Five supervised neural network-based machine learning models with different architectures were trained on the baseline dataset, or the follow-up dataset, or both to predict major bleeding. After training, these machine learning models were tested on the testing set and compared to the conventional clinical models, modified to make them compatible with the available predictor variables in our dataset, including the CHAP, the HAS-BLED, the VTE-BLEED, the RIETE, the ACCP, and the OBRI, which only use the baseline information. Results: Overall, the models that used the follow-up information had a higher area under the Receiver Operating Curve (AUROC) or c-statistic compared to the other models that only relied on the baseline dataset. In particular, the LSTM RNN model was able to achieve AUROC of 81.3% that is more than 10% higher compared to the best performing clinical model. We discovered that the LSTM RNN model mostly relied on features such as number of concomitant medications, years since baseline visit, use of specific antibiotics or antiplatelet agents, and presence of new hypertension to predict bleeding from the follow-up dataset. Furthermore, half of the bleeding events occurred within the first year after patients' baseline visits - a trend reflected in the predictions made by LSTM RNN model. Finally, the models that used both the baseline and the follow-up datasets showed different results depending on their architectures; that is, the simpler ensemble model achieved AUROC of 82.5% while the more complex model had AUROC of 70.8% due to overfitting. Conclusion: We have shown that using time series follow-up data can improve bleeding risk prediction in patients with VTE who are on extended anticoagulant therapy compared to just using the baseline data, and clinicians might benefit from using such an approach. Furthermore, our results indicate that LSTM RNN is a suitable architecture to model routine clinical follow-up data. Finally, we believe using time series data could improve the performance of the other clinical models that are currently based on one-time baseline measurements.

Efficacy, Safety, and Health-Related Quality of Life (HRQOL) in Patients with Sickle Cell Disease (SCD) Who Have Received Lovotibeglogene Autotemcel (Lovo-cel) Gene Therapy: Up to 60 Months of Follow-up

Introduction: Lovo-cel gene therapy uses autologous transplantation of hematopoietic stem and progenitor cells (HSPC) transduced with the BB305 lentiviral vector encoding a modified β-globin gene, which produces an anti-sickling hemoglobin (Hb), HbA T87Q. The phase 1/2 HGB-206 (NCT02140554) and phase 3 HGB-210 (NCT04293185) studies of lovo-cel are the largest clinical trials of gene therapy in SCD to date. We report efficacy and safety from these studies, including the first data from adult and pediatric patients (age 12 to &amp;lt;18 years) in HGB-210, and HRQOL data from HGB-206. Methods: This analysis includes patients from HGB-206 Group C and HGB-210 who received lovo-cel using the current HSPC mobilization and manufacturing process. Patients with SCD and recurrent severe vaso-occlusive events (VOEs) or history of overt stroke underwent plerixafor mobilization and apheresis followed by myeloablative busulfan conditioning and lovo-cel infusion. After 24 months of follow-up post lovo-cel infusion, patients enrolled in the long-term study LTF-307 (NCT04628585). Lab evaluations, SCD-related outcomes (eg, resolution of VOEs), globin response (a composite endpoint evaluating HbA T87Q percentage and total Hb), and safety are reported up to 60 months. An independent Event Adjudication Committee confirmed VOEs met protocol criteria. HRQOL data from Patient-Reported Outcomes Measurement Information System (PROMIS)-57 domains of pain interference, fatigue, and pain intensity are reported up to 48 months. Results:This analysis includes47 patients (HGB-206 Group C, n=36; HGB-210, n=11; male, 59.6%; median [range] age, 23 y [12-38]) who received a lovo-cel infusion as of Feb 13, 2023. Median (range) follow-up was 35.5 months (0.3-61.0). Median (range) time to neutrophil and platelet engraftment was 20 days (12-35) and 35 days (19-136). Peripheral blood vector copy number remained stable (median &amp;gt;1 c/dg through follow-up). Median HbA T87Q levels were ≥4.5 g/dL from 6 months post infusion to last study visit. Median (range) total Hb level increased from 8.7 g/dL (6.1-12.5) at relative baseline to 11.8 g/dL (8.4-15.0) at last visit; median percent HbA T87Q of nontransfused total Hb was ≈40% or more ( Figure). Of 33 evaluable patients (ie, ≥18 months follow-up and ≥4 VOEs in the 2 years before enrollment), 30 (90.9%) and 32 (97.0%) had complete resolution of VOEs and severe VOEs during the 6-18 months post infusion, vs a median (range) of 3.5 (1.5-16.5) and 3.0 (0.5-13.0) events/year in the 2 years before enrollment. Additional efficacy analyses in subgroups (eg, stroke history, α-globin genotype) will be presented. Among patients who had globin response or who had ≥18 months follow-up (n=38), 33 (86.8%) achieved globin response. Hemolysis markers (eg, reticulocytes, total bilirubin, lactate dehydrogenase) approached normal levels. Among all 47 patients, 44 (93.6%) had ≥1 AE of grade ≥3 after lovo-cel infusion; the most common of which were stomatitis (33 [70.2%] patients) and thrombocytopenia (28 [59.6%]). Serious AEs were reported for 26 (55.3%) patients, the most common of which was chronic pain/acute exacerbation of chronic pain (3 [6.4%]; 2 chronic neuropathic pain and 1 chronic pain associated with anxiety). One patient with -α3.7/-α3.7 genotype was diagnosed with myelodysplastic syndrome with stable complete blood counts 30 months post infusion; updated data to be presented. No veno-occlusive liver disease, graft failure, replication-competent lentivirus, or vector-mediated insertional oncogenesis was observed. Lovo-cel treatment regimen largely reflected known side effects of HSPC collection and busulfan conditioning regimen. A total of 25 patients (all from HGB-206 Group C; age ≥18 y) had evaluable HRQOL data. Mean scores for PROMIS-57 domains of pain intensity, pain interference, and fatigue improved (ie, decreased) over time up to 48 months ( Table). Conclusion: One-time treatment with lovo-cel resulted in sustained HbA T87Q production and near-complete resolution of VOEs and severe VOEs up to 18 months post treatment; the safety profile was consistent with underlying SCD and myeloablative conditioning. Patients reported sustained improvements in pain intensity, pain interference, and fatigue. Ongoing long-term follow-up will continue to provide important information on efficacy, safety, and patient experience post lovo-cel treatment.

Updated Protocol for the Phase 3, Randomized, Double-Blinded Lex-210 Study of Four-Factor Prothrombin Complex Concentrate in Patients with Acute Major Bleeding on Factor Xa Inhibitor Therapy

Background and Significance: Despite significantly reduced risk of intracranial hemorrhage compared with vitamin K antagonists, direct oral anticoagulant therapy with factor Xa inhibitors (FXaI) is associated with similar incidences of other major bleeds. Although hemostatic agents such as prothrombin complex concentrates (PCCs) are often used (off-label), the efficacy and safety of PCCs for managing FXaI-related bleeding requires further investigation. This study aims to evaluate superior hemostatic efficacy of high-dose vs low-dose four-factor (4F) PCC (Octaplex®; Octapharma) in adults with FXaI-related major bleeding. Study Design and Methods: LEX-210 (NCT04867837) is a Phase 3, multicenter, prospective, randomized, double-blinded, group-sequential, parallel-group, adaptive design study. Significant modifications have recently been made to the study design. Patients aged ≥18 years with acute major bleeding (e.g., gastrointestinal, intracranial) and baseline anti-factor Xa activity of ≥100 ng/mL are eligible. To increase rate of recruiting suitable patients into the study, the eligibility criteria have been optimized. For inclusion (full criteria in Table 1), baseline anti-factor Xa activity of ≥100 ng/mL may be either confirmed by locally available tests (including retrospectively by the central laboratory) or suspected by the investigator and later confirmed by the central lab. Prospective written informed consent will be obtained from all patients or patients' legally authorized representative prior to enrolment. If this is not possible, in countries outside the US where it is permitted under local regulations or approved by local ethics committees, deferred consent procedures may be applied. Key exclusion criteria (Table 2) include acute trauma for which FXaI reversal alone would not be expected to control bleeding, and thromboembolic events in the last 3 months. In addition, hypersensitivity to heparin and platelet inhibitors are specified. Patients will be excluded if they score &amp;lt;7 on the Glasgow Coma Scale (with allowances for intubation), or have expected survival of &amp;lt;24 hours. While patients scheduled for surgery in &amp;lt;12 hours are excluded, minor surgeries and invasive procedures for diagnostic or therapeutic reasons are allowed, or if intended to address a second (non-index) bleeding event. Patients will be randomized 1:1 to 50 or 15 IU/kg 4F-PCC. The primary objective is to demonstrate superior hemostatic efficacy of the higher dose in patients with major bleeding associated with FXaI. Hemostatic efficacy through 24 hours after receipt of 4F-PCC will be evaluated by an independent data monitoring and endpoint adjudication committee using objective criteria, with a binary outcome of effective or ineffective. Secondary endpoints include change in endogenous thrombin potential (baseline to 1 hour after 4F-PCC), 30-day rates of thromboembolic events, and all-cause mortality. The study is conducted in accordance with the ethical principles laid down in the Declaration of Helsinki The proportion of patients with an effective outcome will be compared between groups using a one-sided z-test. The primary statistical model will be adjusted for the baseline anti-factor Xa activity as determined retrospectively by the central laboratory. A logistic regression model for the success rate using treatment group (dose level) and the anti-factor Xa activity as fixed effects will be used to determine the one-sided z-statistic. LEX-210 launched in Q4 2021 and will be performed across ~60 sites in North America and the European Continent. Target enrollment is ~260 patients, assuming a 30% dropout rate. So far, 26 sites in the US, Italy, Germany, and Spain have been initiated, with 5 patients enrolled. Study completion is anticipated in Q3 2024.

Preliminary Results from a Phase 1 Dose Escalation Study of FHD-286, a Novel BRG1/BRM (SMARCA4/SMARCA2) Inhibitor, Administered As an Oral Monotherapy in Patients with Advanced Hematologic Malignancies

The BRG/Brahma-associated factors (BAF) family of chromatin remodeling complexes (also referred to as the mSWI/SNF complex) regulates the chromatin landscape of the genome. Through its adenosine triphosphate (ATP)-dependent chromatin remodeling activity, BAF complexes regulate the accessibility of gene-control elements, allowing for the binding of transcription factors. Thus, BAF is a major regulator of lineage- and disease-specific transcriptional programs. FHD-286 is a first-in-class, orally administered compound that potently and selectively inhibits the ATPase components of the BAF complexes, SMARCA4 and SMARCA2 (also called BRG1 and BRM, respectively). In preclinical models, acute myeloid leukemia (AML) cell lines were highly sensitive to BAF inhibition. FHD-286-C-002 (NCT04891757) is a multicenter, open-label, Phase 1 dose escalation study designed to determine the safety, tolerability, dose-limiting toxicities (DLTs), and maximum tolerated dose and/or the recommended phase 2 dose(s), as well as to evaluate the preliminary clinical activity of FHD-286, in patients with advanced hematologic malignancies. Patients with relapsed or refractory (R/R) AML or myelodysplastic syndrome (MDS) failing all available standard therapies were eligible to receive FHD-286 doses ranging from 2.5 mg once daily (QD) to 10 mg QD on a continuous dosing regimen. Patients had regularly scheduled assessments to evaluate safety, pharmacokinetics (PK), pharmacodynamics, preliminary clinical activity, and exploratory biomarkers. As of 02 Aug 2022, 40 patients with a median age of 65.5 years (range 25 to 84) with R/R AML (36 patients) or MDS (4 patients) had received at least 1 dose of FHD-286. 67.5% of patients had received ≥3 prior lines of therapy for AML/MDS/other antecedent hematologic disorder, with 22.5% having received ≥5 prior lines. 32.5% of patients had prior hematopoietic stem cell transplant. 65% of patients had adverse risk genetics by 2017 ELN recommendations. 85% of patients experienced a treatment-related adverse event (TRAE) of any grade; the most common (≥20% of patients) were dry mouth (27.5%), increased blood bilirubin (22.5%), and alanine aminotransferase (ALT) increased and rash (20% each). 50% of patients experienced a Grade ≥3 TRAE, the most common of which was increased blood bilirubin (12.5%); stomatitis, ALT increased, differentiation syndrome (DS), and hypocalcemia occurred in 7.5% (each). 2 DLTs were reported: Grade 3 hyperbilirubinemia in 1 patient receiving 5 mg QD and Grade 3 muscular weakness in 1 patient receiving 10 mg QD. Treatment-related DS of any grade was investigator-reported in 4 patients (10%). An independent adjudication committee determined that the rate of suspected DS was 15% (6 patients). 16 patients (15 AML; 1 MDS) had a best overall response of stable disease. Markers of myeloid differentiation with neutrophil recovery and reductions in bone marrow and/or peripheral blasts have been observed in a subset of patients in the study who had a broad range of cytogenetic backgrounds, including patients with enhancer-driven leukemias such as MECOM and KMT2A. Preliminary PK analysis indicates that FHD-286 appears to have a long half-life, at a minimum of &amp;gt;24 hours, and that plasma concentrations of FHD-286 increase with increasing dose. Exploratory flow cytometry assessment of markers of differentiation, hematopoietic stem cell identity, and apoptosis suggested dose-dependent target engagement. Additionally, exploratory sequencing analysis on bone marrow blasts revealed comprehensive impacts on AML-specific expression pathways and stemness genes in response to FHD-286. An exposure-response analysis using the percentage of peripheral blasts showed a trend toward lower blast count with higher FHD-286 area-under-the-curve. Enrollment into the single-agent dose escalation phase of the study is complete. Based on nonclinical, translational, and single-agent clinical data, FHD-286 in combination with decitabine or low-dose cytarabine is being evaluated in the combination dose escalation phase of the study.

Bimekizumab in Patients with Moderate to Severe Plaque Psoriasis: Analysis of Mental Health and Associated Disorders

Introduction: Patients (pts) with psoriasis have a greater risk of depression and suicidality than the general population.1 Here, we report Week (Wk)16 and longer-term depression and suicidal ideation and behavior (SIB) data in bimekizumab (BKZ)-treated pts with moderate to severe plaque psoriasis.&#x0D; Procedure/study: The Patient Health Questionnaire (PHQ)-9, scored 0–27, measured depression severity monthly to Wk16 (regular intervals during BE BRIGHT open-label extension);2,3 higher scores indicate worse depression. PHQ-9 data were pooled from Wk0–16 of BE VIVID/BE READY (BKZ 320mg every 4 weeks [Q4W] vs. placebo [PBO]);4,5 3-year BE BRIGHT data are also reported.3 An independent Neuropsychiatric Adjudication Committee evaluated potential SIB treatment-emergent adverse events (TEAEs) and elevated PHQ-9 scores. Adjudicated SIB (suicide completion/attempt/ideation) incidence/100 pt-years (yrs; PY) was pooled from nine BKZ phase 2/3/3b trials in psoriasis, including up to 5 yrs’ exposure.3–11&#x0D; Results: At Wk16, mean reduction from baseline in PHQ-9 with BKZ Q4W (N=670) vs. PBO (N=169) was 1.3 vs. 0.3; overall mean Wk16 scores were 1.2 and 2.4 for BKZ and PBO. Low mean BKZ PHQ-9 scores were maintained over 3 yrs of BE BRIGHT following the feeder studies (Wk144: 1.2). At Wk16, 92.9% of BKZ pts scored 0–4 in PHQ-9 (no/minimal depression) vs. 81.1% of PBO pts; 1.3% vs. 6.3% scored ≥10 (moderate–severe depression). Through Wk16, 0.7% BKZ vs. 4.1% PBO pts scored ≥15 (moderately severe–severe) in PHQ-9 at any visit. Over 7,166 PY of BKZ exposure (N=2,480), the rate of adjudicated SIB TEAEs was 0.126/100 PY.&#x0D; Conclusion: PHQ-9 scores were low through Wk16 and remained low with longer BKZ exposure. The vast majority of BKZ pts had no/minimal depression at Wk16. The long-term incidence rate of adjudicated SIB with BKZ was low and similar to the general psoriasis population (range: 0.09–0.54/100 PY).1,12&#x0D; Funding: UCB Pharma.

The Effect of Posterior Pericardiotomy on the Incidence of Atrial Fibrillation After Cardiac Surgery-Extended Follow-Up study (PALACS-EF): rationale and design.

Postoperative atrial fibrillation (POAF) is the most common complication of cardiac surgery and has been associated with increased postoperative morbidity and hospital costs. The Posterior left pericardiotomy for the prevention of AtriaL fibrillation After Cardiac Surgery (PALACS) trial found that posterior pericardiotomy significantly reduced the incidence of POAF (17% vs. 32%, P < 0.001). We present the protocol for The Effect of Posterior Pericardiotomy on the Incidence of Atrial Fibrillation After Cardiac Surgery-Extended Follow-Up study (PALACS-EF): a prospective, extended follow-up of the original PALACS trial. The aim of PALACS-EF is to gain more data regarding the effect of posterior pericardiotomy on postdischarge clinical outcomes. The primary outcome is the time to the first occurrence of the composite of all-cause mortality or hospital cardiovascular readmission. The key secondary outcome is the time to the first occurrence of the composite of all-cause mortality and all-cause hospital readmission. Hospital readmission, myocardial infarction, stroke, transient ischaemic attack, heart failure, systemic embolism, or new arrhythmias with onset since 30-day follow-up will also be recorded. All 420 patients enrolled in the PALACS trial will be included; extended follow-up will be conducted via telephone by blinded research personnel utilizing a standardized script to ensure uniformity and completeness of follow-up. If an event has occurred, documentation will be obtained, and an independent adjudication committee blinded to group assignment will adjudicate outcome events. Results will be reported when a median follow-up of 5 years is achieved. PALACS-EF will provide data to answer the question of whether posterior pericardiotomy improves postdischarge outcomes in patients undergoing cardiac surgery, and it will provide information on the relationship between POAF and adverse postdischarge outcomes including mortality, hospitalization, heart failure, and stroke. PALACS: NCT02875405, PALACS-EF: NCT05903222.

France LILI (LIthopLastie Intracoronaire)

BackgroundIntravascular lithotripsy (IVL) is a novel and appealing device for the preparation of coronary calcified lesions before stenting. This technology has received CE mark and FDA approval, according to the data of the CAD studies. However, these clinical trials show numerous limits as the exclusion of a subset of lesions (Left main, CTO, in stent restenosis …) and patients’ over-selection. In this view, applications of IVL results in daily practice are debatable according to the lack of evidence in unselected patients. MethodsFRANCE-LILI is a prospective national academic registry evaluating the safety and effectiveness of adjunctive intravascular lithotripsy in coronary angioplasty in an all-comers patient population in France. The registry is registered with the ClinicalTrials.gov database (NCT05113407) and managed by the French Coronary Atheroma and Interventional Cardiology Group (GACI) of the French Society of Cardiology (FSC).France LILI will prospectively enroll 500 subjects. The primary endpoint is target vessel failure (TVF) at one year, defined as a composite of cardiac death, myocardial infarction (MI) according to the Academic Research Consortium-2 (ARC-2) definition (except for an MI clearly attributed to a non-target vessel) and revascularization of the target vessel. All endpoints are evaluated and confirmed by an independent adjudication committee. ConclusionThis national prospective academic registry will provide fruitful data on IVL in an unselected population of complex coronary lesions.

Clinical and imaging features of interstitial lung disease in cancer patients treated with trastuzumab deruxtecan

BackgroundInterstitial lung disease/pneumonitis (ILD/pneumonitis) has been identified as a drug-related adverse event of special interest of trastuzumab deruxtecan (T-DXd), but there were a few reports of T-DXd-related ILD/pneumonitis in clinical practice.MethodsBetween May 25, 2020 (the launch of T-DXd in Japan) and February 24, 2022, there were 287 physician-reported potential ILD/pneumonitis cases from the Japanese post-marketing all-case surveillance. By February 27, 2022, an independent adjudication committee assessed 138 cases and adjudicated 130 cases as T-DXd-related ILD/pneumonitis. The clinical features and imaging characteristics of these cases were evaluated.ResultsThe majority of adjudicated T-DXd-related ILD/pneumonitis cases were grade 1 or 2 (100/130, 76.9%). The most common radiological pattern types observed were organizing pneumonia patterns (63.1%), hypersensitivity pneumonitis patterns (16.9%), and diffuse alveolar damage (DAD) patterns (14.6%). Eleven cases (8.5%) from 130 resulted in death; the majority of these (8/11, 72.7%) had DAD patterns. The overall proportion of recovery (including the outcomes of recovered, recovered with sequelae, and recovering) was 76.9%, and the median time to recovery was 83.5 days (interquartile range: 42.25–143.75 days). Most cases (59/71, 83.1%) that were treated with corticosteroids were considered responsive to treatment.ConclusionsThis is the first report to evaluate T-DXd-related ILD/pneumonitis cases in clinical practice. Our findings are consistent with previous reports and suggest that patients with DAD patterns have poor outcomes. Evaluation of a larger real-world dataset may further identify predictors of clinical outcome.

Safety of high loading doses of teicoplanin: POSY-TEICO, a prospective, multicentre, observational study

Teicoplanin is used for treating infections caused by Gram-positive bacteria. The POSY-TEICO study assessed the safety of a high loading dose (HLD) of teicoplanin (12mg/kg twice daily) in a real-world setting. This prospective study was conducted across six countries in Europe and enrolled adults prescribed HLD of teicoplanin between 2016-2019. The primary objective was to determine the incidence of nephrotoxicity following HLD of teicoplanin over loading dose period. An independent clinical adjudication committee (ICAC) assessed all study outcomes related to nephrotoxicity. The study included 300 patients (males, 68.3%), with a mean age of 63.1 years and median teicoplanin treatment duration of 16 days (interquartile range: 9-38). Number of patients with bone and joint infection, infective endocarditis, and other severe infections was 176, 36, and 80, respectively. During loading dose period, 41 (13.8%) patients received 3 HLDs and 246 (82.8%) received ≥4 HLDs. Overall, 28 (11.0%) patients (95%CI, 7.4-15.5) experienced nephrotoxicity during loading and 10 (6.9%) patients (95%CI, 3.4-12.4) during maintenance dose periods. Number of patients who experienced nephrotoxicity certainly or possibly related to teicoplanin according to the ICAC was 20 (7.9%; 95%CI, 4.9-11.9), 8 (5.6%; 95%CI, 2.4-10.7) and 33 (12.4%; 95%CI, 8.7-16.9) across three study periods. HLD of teicoplanin had an acceptable safety profile in patients treated for bone and joint infection, infective endocarditis, and other severe infections and no increased risk of nephrotoxicity was observed. However, patients should be closely monitored when HLDs are administered.

The structured ambulatory post-stroke care program for outpatient aftercare in patients with ischaemic stroke in Germany (SANO): an open-label, cluster-randomised controlled trial

Patients with ischaemic stroke are at risk of recurrent stroke. In this study, we aimed to compare the effect of a structured ambulatory post-stroke care programme versus usual care on recurrent vascular events and death and control of cardiovascular risk factors. We did a prospective, open-label, cluster-randomised controlled trial (SANO) at stroke centres in regions of Germany. A cluster was defined as a region in which acute stroke care is provided by a participating stroke centre. Patients were eligible for participation if they were aged 18 years or older, had no severe disabilities before the index stroke (modified Rankin scale 0-1), had at least one modifiable cardiovascular risk factor, and presented within 14 days of symptom onset of their first ischaemic stroke. The participating regions were randomly assigned (1:1) to the intervention and control group (usual care) by the statistician using block randomisation (block sizes of six), stratified by rural and urban regions. In intervention regions, a cross-sectoral multidisciplinary network was established to provide a 1-year organisational and patient-centred intervention. Due to the type of intervention, masking of participants and study physicians was not possible. Endpoint adjudication was performed by an independent endpoint adjudication committee who were masked to cluster allocation. The primary endpoint was a composite of recurrent stroke, myocardial infarction, and all-cause death within 12 months after baseline assessment, assessed in the modified intention-to-treat (mITT) population, which included all patients who did not withdraw consent and completed the primary endpoint assessment at 12 months. This study was registered with the German Clinical Trials Register, DRKS00015322. Between Jan 1, 2019 and Dec 22, 2020, 36 clusters were assessed for eligibility, of which 30 were randomly assigned to the intervention group (n=15 clusters) or control group (n=15 clusters). No clusters dropped out of the study. 1203 (86%) of 1396 enrolled patients in the intervention group and 1283 (92%) of 1395 enrolled patients in the control group were included in the mITT population. The primary endpoint was confirmed in 64 (5·3%) of 1203 patients in the intervention group and 80 (6·2%) of 1283 patients in the control group (unadjusted odds ratio [OR] 0·80 [95% CI 0·49-1·30]; adjusted OR [aOR] 0·95 [95% CI 0·54-1·67]). All-cause deaths occurred in 31 (2·4%) of 1203 patients in the intervention group and 12 (1·0%) of 1283 patients in the control group. The incidence of serious adverse events was higher in the intervention group (266 [23·1%] of 1151) than the control group (106 [9·2%] of 1152). Falls (134 [11·4%] of 1203 patients in the intervention group; 39 [3·3%] of 1152 patients in the control group), hypertensive crisis (55 [4·7%]; 34 [2·8%]), and diagnosis of depression (51 [4·3%]; 13 [1·1%]) were the most frequent adverse events in both groups. No differences were identified in the rate of readmission to hospital between groups. No differences were identified between patients with ischaemic stroke in the intervention group and control group with regard to the incidence of vascular events 1 year after baseline assessment, despite positive effects with regard to the control of some cardiovascular risk factors. Longer-term effects and other potentially favourable effects on stroke-related sequelae and quality of life require further evaluation. Innovation Fund of the Federal Joint Committee.

Performance of 11 Host Biomarkers Alone or in Combination in the Diagnosis of Late-Onset Sepsis in Hospitalized Neonates: The Prospective EMERAUDE Study.

Despite the high prevalence of late-onset sepsis (LOS) in neonatal intensive care units, a reliable diagnosis remains difficult. This prospective, multicenter cohort study aimed to identify biomarkers early to rule out the diagnosis of LOS in 230 neonates ≥7 days of life with signs of suspected LOS. Blood levels of eleven protein biomarkers (PCT, IL-10, IL-6, NGAL, IP-10, PTX3, CD14, LBP, IL-27, gelsolin, and calprotectin) were measured. Patients received standard of care blinded to biomarker results, and an independent adjudication committee blinded to biomarker results assigned each patient to either infected, not infected, or unclassified groups. Performances of biomarkers were assessed considering a sensitivity of at least 0.898. The adjudication committee classified 22% of patients as infected and all of these received antibiotics. A total of 27% of the not infected group also received antibiotics. The best biomarkers alone were IL-6, IL-10, and NGAL with an area under the curve (95% confidence interval) of 0.864 (0.798-0.929), 0.845 (0.777-0.914), and 0.829 (0.760-0.898), respectively. The best combinations of up to four biomarkers were PCT/IL-10, PTX3/NGAL, and PTX3/NGAL/gelsolin. The best models of biomarkers could have identified not infected patients early on and avoided up to 64% of unjustified antibiotics. At the onset of clinical suspicion of LOS, additional biomarkers could help the clinician in identifying non-infected patients.

Letermovir vs Valganciclovir for Prophylaxis of Cytomegalovirus in High-Risk Kidney Transplant Recipients

Valganciclovir for 200 days is standard care for cytomegalovirus (CMV) prophylaxis in high-risk CMV-seronegative kidney transplant recipients who receive an organ from a CMV-seropositive donor, but its use is limited by myelosuppression. To compare the efficacy and safety of letermovir with valganciclovir for prevention of CMV disease in CMV-seronegative kidney transplant recipients who receive an organ from a CMV-seropositive donor. Randomized, double-masked, double-dummy, noninferiority, phase 3 trial in adult CMV-seronegative kidney transplant recipients who received an organ from a CMV-seropositive donor at 94 participating sites between May 2018 and April 2021 (final follow-up in April 2022). Participants were randomized in a 1:1 ratio (stratified by receipt of lymphocyte-depleting induction immunosuppression) to receive letermovir, 480 mg, orally daily (with acyclovir) or valganciclovir, 900 mg, orally daily (adjusted for kidney function) for up to 200 days after transplant, with matching placebos. The primary outcome was CMV disease, confirmed by an independent masked adjudication committee, through posttransplant week 52 (prespecified noninferiority margin, 10%). CMV disease through week 28 and time to onset of CMV disease through week 52 were secondary outcomes. Exploratory outcomes included quantifiable CMV DNAemia and resistance. The rate of leukopenia or neutropenia through week 28 was a prespecified safety outcome. Among 601 participants randomized, 589 received at least 1 dose of the study drug (mean age, 49.6 years; 422 [71.6%] men). Letermovir (n = 289) was noninferior to valganciclovir (n = 297) for prevention of CMV disease through week 52 (10.4% vs 11.8% of participants with committee-confirmed CMV disease; stratum-adjusted difference -1.4% [95% CI, -6.5% to 3.8%]). No participants who received letermovir vs 5 participants (1.7%) who received valganciclovir developed CMV disease through week 28. Time to onset of CMV disease was comparable between the groups (hazard ratio, 0.90 [95% CI, 0.56-1.47]). Quantifiable CMV DNAemia was detected in 2.1% of participants in the letermovir group vs 8.8% in the valganciclovir group by week 28. Of participants evaluated for suspected CMV disease or CMV DNAemia, none (0/52) who received letermovir and 12.1% (8/66) who received valganciclovir had resistance-associated substitutions. The rate of leukopenia or neutropenia through week 28 was lower with letermovir vs valganciclovir (26% vs 64%; difference, -37.9% [95% CI, -45.1% to -30.3%]; P < .001). Fewer participants in the letermovir group than the valganciclovir group discontinued prophylaxis due to adverse events (4.1% vs 13.5%) or drug-related adverse events (2.7% vs 8.8%). Among adult CMV-seronegative kidney transplant recipients who received an organ from a CMV-seropositive donor, letermovir was noninferior to valganciclovir for prophylaxis of CMV disease over 52 weeks, with lower rates of leukopenia or neutropenia, supporting its use for this indication. ClinicalTrials.gov Identifier: NCT03443869; EudraCT: 2017-001055-30.

Low-density lipoprotein electronegativity and risk of death after acute coronary syndromes: A case-cohort analysis

Background and aimsLow-density lipoprotein (LDL)-cholesterol (LDL-C) promotes atherosclerotic cardiovascular disease (ASCVD), with changes in LDL electronegativity modulating its pro-atherogenic/pro-thrombotic effects. Whether such alterations associate with adverse outcomes in patients with acute coronary syndromes (ACS), a patient population at particularly high cardiovascular risk, remains unknown. MethodsThis is a case-cohort study using data from a subset of 2619 ACS patients prospectively recruited at four university hospitals in Switzerland. Isolated LDL was chromatographically separated into LDL particles with increasing electronegativity (L1-L5), with the L1-L5 ratio serving as a proxy of overall LDL electronegativity. Untargeted lipidomics revealed lipid species enriched in L1 (least) vs. L5 (most electronegative subfraction). Patients were followed at 30 days and 1 year. The mortality endpoint was reviewed by an independent clinical endpoint adjudication committee. Multivariable-adjusted hazard ratios (aHR) were calculated using weighted Cox regression models. ResultsChanges in LDL electronegativity were associated with all-cause mortality at 30 days (aHR, 2.13, 95% CI, 1.07–4.23 per 1 SD increment in L1/L5; p=.03) and 1 year (1.84, 1.03–3.29; p=.04), with a notable association with cardiovascular mortality (2.29; 1.21–4.35; p=.01; and 1.88; 1.08–3.28; p=.03). LDL electronegativity superseded several risk factors for the prediction of 1-year death, including LDL-C, and conferred improved discrimination when added to the updated GRACE score (area under the receiver operating characteristic curve 0.74 vs. 0.79, p=.03). Top 10 lipid species enriched in L1 vs. L5 were: cholesterol ester (CE) (18:2), CE (20:4), free fatty acid (FA) (20:4), phosphatidyl-choline (PC) (36:3), PC (34:2), PC (38:5), PC (36:4), PC (34:1), triacylglycerol (TG) (54:3), and PC (38:6) (all p < .001), with CE (18:2), CE (20:4), PC (36:3), PC (34:2), PC (38:5), PC (36:4), TG (54:3), and PC (38:6) independently associating with fatal events during 1-year of follow-up (all p < .05). ConclusionsReductions in LDL electronegativity are linked to alterations of the LDL lipidome, associate with all-cause and cardiovascular mortality beyond established risk factors, and represent a novel risk factor for adverse outcomes in patients with ACS. These associations warrant further validation in independent cohorts.