Non-interventional Trial Research Articles

Patient satisfaction with radio-frequency identification (RFID) tag localization compared with wire localization for nonpalpable breast lesions: the RFID trial

BackgroundMost breast cancers are detected at an early stage in which case conservative surgery is indicated. An accurate preoperative localization technique is essential for conservative surgery of non-palpable breast lesions. Currently, the gold standard technique is wire localization (WL). However, this technique has well-known drawbacks. Several wire-free techniques have been developed to overcome these drawbacks; one technique is localisation by Radiofrequency Identification (RFID). The purpose of this clinical trial was to assess the superiority of RFID tags (HOLOGIC) in terms of patient satisfaction, over wire localization of non-palpable breast lesions.MethodsThis was a single-centre, prospective, controlled and non-interventional trial. Patients were followed from their inclusion at the time of the preoperative consultation to the postoperative consultation, one month after surgery. Data on anxiety and satisfaction was collected from patients and clinicians using questionnaires, and clinical data was collected from the medical files. The primary outcome was the patients’ satisfaction scores, assessed using a visual analogue scale.ResultsEighty patients were sequentially enrolled in two groups: the wire group (n = 40) and the RFID group (n = 40). One patient from the RFID group was excluded from the analysis because of a substantial migration during deployment. On a 10-point Visual Analogue Scale, the patients’ median satisfaction score was 9.8 (IQR = 1.32) for the wire group and 10 (IQR = 0.07) for the RFID group (p < 0.001). A reduction in pain between device insertion and surgery was observed in the RFID group (p = 0.009). The median placement time was shorter in the RFID group (15 min, IQR = 6) than in the wire group (20 min, IQR = 30) (p = 0.01).ConclusionOur results show a statistically significant difference in median patient satisfaction score with the localization of non-palpable breast cancer lesions using RFID tags compared to the use of the WL. Although our results did not show clinically significant outcomes in terms of satisfaction, RFID tags are a reliable alternative to WL and simplify the organization of patients’ healthcare trajectories.Trial registrationClinicalTrials.gov ID; NCT04750889 registered on February 11, 2021. https://clinicaltrials.gov/ct2/show/NCT04750889?term=rfid&draw=2&rank=1

The Progression of Mycosis Fungoides During Treatment with Mogamulizumab: A BIO-MUSE Case Study of the Tumor and Immune Response in Peripheral Blood and Tissue.

Background/objectives: Mycosis fungoides (MF) is a rare malignancy, with an indolent course in the early stages of the disease. However, due to major molecular and clinical heterogeneity, patients at an advanced stage of the disease have variable responses to treatment and considerably reduced life expectancy. Today, there is a lack of specific markers for the progression from early to advanced stages of the disease. To address these challenges, the non-interventional BIO-MUSE trial was initiated. Here, we report on a case study involving one patient, where combined omics analysis of tissue and blood was used to reveal the unique molecular features associated with the progression of the disease. Methods: We applied 10× genomics-based single-cell RNA sequencing to CD3+ peripheral T-cells, combined with T-cell receptor sequencing, to samples collected at multiple timepoints during the progression of the disease. In addition, GeoMx-based digital spatial profiling of T-helper (CD3+/CD8-), T-cytotoxic (CD3+/CD8+), and CD163+ cells was performed on skin biopsies. Results. The results pinpoint targets, such as transforming growth factor β1, as some of the mechanisms underlying disease progression, which may have the potential to improve patient prognostication and the development of precision medicine efforts. Conclusions: We propose that in patients with MF, the evolution of the malignant clone and the associated immune response need to be studied jointly to define relevant strategies for intervention.

Concizumab prophylaxis in people with haemophilia A or haemophilia B without inhibitors (explorer8): a prospective, multicentre, open-label, randomised, phase 3a trial

Concizumab is an anti-tissue factor pathway inhibitor monoclonal antibody in development as a once-daily, subcutaneous prophylaxis for patients with haemophilia A or haemophilia B with or without inhibitors. We aimed to assess the efficacy and safety of concizumab in patients with haemophilia A or B without inhibitors. Here we report the results from the confirmatory analysis cutoff. This prospective, multicentre, open-label, randomised, phase 3a trial (explorer8) was conducted at 69 investigational sites in 31 countries. Eligible patients were male, aged 12 years or older, and had congenital severe haemophilia A or moderate or severe haemophilia B without inhibitors and with documented treatment with clotting factor concentrate in the 24 weeks before screening. The trial was paused because of non-fatal thromboembolic events in three patients (two from this trial [explorer8] and one from a related trial in haemophilia with inhibitors [explorer7; NCT04083781]) and restarted with mitigation measures, including a revised dosing regimen of subcutaneous concizumab at 1·0 mg/kg loading dose on day 1 and subsequent daily doses of 0·20 mg/kg from day 2, with options to decrease to 0·15 mg/kg, stay on 0·20 mg/kg, or increase to 0·25 mg/kg on the basis of concizumab plasma concentration measured after 4 weeks on concizumab. Patients recruited after treatment restart were randomly assigned 1:2 using an interactive web response system to receive no prophylaxis and continue on-demand clotting factor (group 1) or concizumab prophylaxis (group 2). The primary endpoints were the number of treated spontaneous and traumatic bleeding episodes for patients with haemophilia A and haemophilia B separately, assessed at the confirmatory analysis cutoff in randomly assigned patients. Analyses were by intention-to-treat. There were two additional groups containing non-randomly-assigned patients: group 3 contained patients who entered the trial before the trial pause and were receiving concizumab in the phase 2 trial (explorer5; NCT03196297), and group 4 contained patients who received previous clotting factor concentrate prophylaxis or on-demand treatment in the non-interventional trial (explorer6; NCT03741881), patients randomly assigned to groups 1 or 2 before the treatment pause, and patients from explorer5 enrolled after the treatment pause. The safety analysis set contained all patients who received concizumab. Superiority of concizumab over no prophylaxis was established if the two-sided 95% CI of the treatment ratio was less than 1 for haemophilia A and for haemophilia B. This trial is registered with ClinicalTrials.gov, NCT04082429, and its extension part is ongoing. Patients were recruited between Nov 13, 2019 and Nov 30, 2021; the cutoff date for the analyses presented was July 12, 2022. 173 patients were screened, of whom 148 (86%) were randomly assigned or allocated to the four groups in the study after trial restart on Sept 30, 2020 (nine with haemophilia A and 12 with haemophilia B in group 1; 18 with haemophilia A and 24 with haemophilia B in group 2; nine with haemophilia A in group 3; and 46 with haemophilia A and 30 with haemophilia B in group 4). The estimated mean annualised bleeding rate ratio for treated spontaneous and traumatic bleeding episodes during concizumab prophylaxis versus no prophylaxis was 0·14 (95% CI 0·07-0·29; p<0·0001) for patients with haemophilia A and 0·21 (0·10-0·45; p<0·0001) for patients with haemophilia B. The most frequent adverse events in patients who received concizumab were SARS-CoV-2 infection (19 [13%] of 151 patients), an increase in fibrin D-dimers (12 [8%] patients), and upper respiratory tract infection (ten [7%] patients). There was one fatal adverse event possibly related to treatment (intra-abdominal haemorrhage in a patient from group 4 with haemophilia A with a long-standing history of hypertension). No thromboembolic events were reported between the trial restart and confirmatory analysis cutoff. Concizumab was effective in reducing the bleeding rate compared with no prophylaxis and was considered safe in patients with haemophilia A or B without inhibitors. The results of this trial suggest that concizumab has the potential to be one of the first subcutaneous treatment options for patients with haemophilia B without inhibitors. Novo Nordisk.

Changes in Human Meibum Lipid Composition Related to the Presence and Severity of Meibomian Gland Dysfunction.

Purpose: Changes in meibum composition and quantity in meibomian gland dysfunction (MGD) result in tear film instability and dry eye. This exploratory study aimed to identify changes in (O-acyl)-ω-hydroxy fatty acid (OAHFA) and hydrocarbon chain (HC) unsaturation levels in meibum related to the presence and severity of MGD. Methods: Meibum samples were collected from 3 cohorts of adults with no MGD, mild-to-moderate MGD, and severe MGD in a noninterventional clinical trial (NCT01979887). OAHFAs, cholesterol esters (CE), HC unsaturation, and HC length in the meibum samples were quantified with 1H-nuclear magnetic resonance spectroscopy using 2 methods of normalization. Results: Meibum samples from 62 subjects were analyzed: 21 non-MGD, 21 mild-to-moderate MGD, and 20 severe MGD. Meibum OAHFA and CE levels and HC unsaturation were reduced with increasing severity of MGD, with most pairwise comparisons significant (P < 0.05, t-tests), following the order non-MGD > mild-to-moderate MGD > severe MGD. Regardless of the resonances used for normalization, each pairwise comparison of OAHFA, CE, and HC unsaturation levels in MGD (combined severities) versus non-MGD samples was significant (P < 0.01, t-test). Analysis using various normalization equations showed reductions of 20%-22% for OAHFAs, 51%-57% for CE, and 36%-66% for HC unsaturation in MGD (combined severities) compared with non-MGD. HC length was not altered in MGD (combined severities) compared with non-MGD samples (t-test). Conclusions: Meibum OAHFA, CE, and HC unsaturation levels were reduced in MGD and were lowest in the severe MGD cohort. These findings may contribute to the understanding of the pathophysiology of MGD.

Efficacy of rabeprazole for the treatment of gastroesophageal reflux disease in a 7-day non-interventional trial

To evaluate the efficacy of seven-day treatment with rabeprazole (Razo®) 20 mg once daily in patients with NERD and esophagitis based on monitoring the results of pH-impedancemetry of the stomach and esophagus and assessment of clinical symptoms. Thirty patients with typical GERD manifestations were examined. The study included patients who underwent pH-impedancemetry, endoscopic examination, and were prescribed treatment with rabeprazole at a dose of 20 mg once a day. Clinical monitoring was performed during three visits: before treatment, after 3 days, and after 7 days of treatment. Control pH-impedancemetry was performed after 7 days of therapy. The third visit was the endpoint of the study. After 7 days of treatment, the response rate for heartburn was 86.7% in the overall group of patients with GERD, 94.4% in those with NERD, and 75.0% in patients with esophagitis stage A and B. After 7 days of therapy with rabeprazole, we registered a significant decrease in the total number of refluxes (from 88 to 54; p<0.001), the number of acid refluxes (from 53 to 22; p<0.001), the DeMeester index (from 23.81 to 7.62; p<0.001), and AET (from 7.54 to 2.01; p<0.001) in the esophagus and an increase in the median daily pH (from 1.8 to 5.4; p<0.001) and the time with pH>4 in the stomach (from 2.57 hours and 10.7% up to 12.3 hours and 51.3%; p<0.001). 7-day therapy with rabeprazole was accompanied by a significant improvement in GERD patients in all parameters of quality of life. 100% of patients with GERD rated their satisfaction with therapy as "good" and "very good". As a result of 7-day therapy of patients with NERD and esophagitis with Razo® at a dose of 20 mg per day, an excellent clinical response was obtained, confirmed by a marked optimization of pH-impedancemetry parameters.

Eosinophilia as Monitoring Parameter for Chronic Graft-versus-Host Disease and Vitamin D Metabolism as Monitoring Parameter for Increased Infection Rates in Very Long-Term Survivors of Allogeneic Stem Cell Transplantation—A Prospective Clinical Study

Background: Our aim is to investigate cardiovascular risk factors, chronic graft-versus-host disease (CGvHD), and vitamin D metabolism in very long-term survivors of adult allogeneic stem cell transplantation (alloSCT). Methods: This study is a prospective unicentric, non-interventional trial. The detailed study protocol is available via the WHO Clinical Trial Registry. Results: We were able to include 33 patients with a mean age of 60.5 years (SD 11.1). Acute myeloid leukemia (AML) was the most frequent underlying disease (n = 12; 36.4%). The median survival time was 9.0 years (IQR 8.5–13.0). Relevant cardiovascular risk factors in the study population are the body mass index, cholesterol, LDL cholesterol, and lipoprotein(a). Cardiovascular risk factors have no significant impact on HRQoL. CGvHD of the skin as a limited disease was present in six patients (18.2%), and it has no impact on HRQoL. CGvHD was significantly associated with eosinophilia in peripheral blood (p = 0.003). Three patients (9.1%) had a shortage of calcitriol, and one patient (3.0%) took calcium substitution. The shortage is significantly associated with increased infection rates (p = 0.038). Conclusions: Cardiovascular risk factors and CGvHD need to be closely monitored. Eosinophilia might be a good and convenient monitoring parameter for CGvHD.

Selective opioid agonist Taphalgin® as a component of postoperative analgesia in various surgical areas: “NIKITA” observational multicenter study

Introduction. The role of peptides in antinociceptive system regulation has became a subject of interest for scientists worldwide. The first registered peptide analgesic tyrosyl-D-arginyl-phenylalanyl-glycinamide acetate which currently can be used in clinical practice was developed in Russia under the name Taphalgin® (PharmFirma “Sotex”, Russia). The effectiveness and safety of this pharmaceutical in postoperative pain management was evaluated in the all-Russia multicenter prospective observation program NICITA (Non-interventional Clinical Trial of Taphalgin ®).Aim. To analyze the effectiveness and safety of Taphalgin® in postoperative pain management in various surgical fields.Materials and methods. The observational program NICITA included 887 patients including patients with malignant tumors of various locations from 15 study centers in different Russian cities. All patients underwent surgical interventions in various anatomical areas under general, regional and combination anesthesia. The principal scheme of postoperative pain management was based on the multimodal approach which included peptide opioid agonist alongside acetaminophen, cyclooxygenase inhibitors in combination with regional anesthesia or without it. The study also included patients who underwent small-volume surgeries, and pain was managed through Taphalgin® monotherapy with subsequent switch to cyclooxygenase inhibitors. The primary endpoint of the NICITA observational program was response to therapy after the first Taphalgin® administration. Decreased pain syndrome per the numerical rating scale 15–60 min after subcutaneous injection and maintenance of analgesic effect 3 h later were considered treatment response. The secondary endpoints included mean time to analgesia start after administration of the 1st single drug dose (in min), duration of effect, types and frequency of adverse reactions including serious in the central nervous system, pulmonary system, gastrointestinal tract developed during the observational program, as well as patient and research physician satisfaction with pain management. To evaluate the significance of pain intensity change at rest and in motion in time, analysis of variance with repeat measurements was used; for pairwise comparison of two time periods, Student’s t-test for dependent samples was used. The differences were considered significant at p = 0.05.Results. Statistically significant decrease in pain intensity in the total patient group was observed 15 minutes after Taphalgin® administration; it reached its minimum 40 min after the injection (р &lt;0.05). The percentage of patients responding to analgesic therapy with Taphalgin® was 96.5 %. During administration of the drug, insignificant decrease (10–15 mmHg) in arterial blood pressure (1.7 % of cases) and vertigo (1 % of cases) were observed. In some patients, several adverse reactions were observed. Satisfaction with analgesic effect of Taphalgin® was relatively high both in patients and research physicians.Conclusion. Taphalgin® has pronounced analgesic effect and is effective for pain management after surgical interventions of various volumes and injury level. The use of this drug is associated with low rate of adverse reactions and absence of pulmonary depression characterizing opioid agonists. Therefore, Taphalgin® can be recommended for clinical use for postoperative pain management after various types of surgical interventions.

The Beijing angle closure progression study: design and methodology.

The purpose of this study is to summarize the design and methodology of a large-scale trial in northern China, the Beijing Angle Closure Progression Study (BAPS). This trial is designed to explore the 5-year incidence of primary angle-closure suspect (PACS) progressing to primary angle-closure (PAC) or primary angle-closure glaucoma (PACG) and to determine the possible risk factors of disease progression. The BAPS is a clinic-based, multicenter, noninterventional trial conducted on a sample of urban Chinese adults. Consecutive eligible patients who meet PACS diagnostic criteria will be recruited from eight participating centers, with the trial commencing on August 4, 2022. The target sample size is set at 825 subjects, with follow up planned for a minimum period of 5 years. Baseline examination will include presenting visual acuity, best corrected visual acuity, intraocular pressure (IOP), undilated slit-lamp biomicroscopy, stereoscopic evaluation of the optic disc, visual field test, optical coherence tomography evaluation of retinal nerve fiber layer, ultrasound biomicroscopy and IOLMaster. Questionnaires will also be used to collect detailed personal history. Patients are scheduled to visit the glaucoma clinic every 12 months and may visit the emergency room in case of acute attack of angle closure. Study endpoints include acute PAC episodes, elevated IOP, peripheral anterior synechiae, glaucomatous visual field defect, or glaucomatous abnormality of optic nerve. The BAPS will provide data on the 5-year incidence of PACS progressing to PAC or PACG and determine the risk factors for disease progression. This study will also help redefine high-risk patients with PACS.

TOWARDS Study: Patient-Derived Xenograft Engraftment Predicts Poor Survival in Patients With Newly Diagnosed Triple-Negative Breast Cancer.

Assessing risk of recurrence for nonmetastatic triple-negative breast cancer (TNBC) is a key determinant of therapeutic strategy. The best predictor of recurrence risk is failure to achieve a pathologic complete response after preoperative chemotherapy, but it imperfectly correlates with the definitive end points of relapse-free and overall survival (OS). The inability to accurately predict recurrence has led to increasingly toxic treatment regimens for patients with early-stage TNBC. Better assays for recurrence risk are needed to tailor aggressive therapy for patients who need it and avoid overtreatment and unnecessary toxicity for those at low risk. The purpose of this study was to determine if patient-derived xenograft (PDX) engraftment of newly diagnosed breast tumors can serve as an accurate predictor of recurrence and death from breast cancer. This study was a blinded noninterventional trial comprising 80 patients with newly diagnosed, nonmetastatic, estrogen receptor (ER)-negative or ER-low breast cancer. PDX engraftment was strongly associated with relapse in 1 year: 8 of 18 (44.4%) patients whose tumors engrafted relapsed versus 1 of 62 (1.6%) patients whose tumors did not engraft (P < .0001). Patients whose tumors engrafted had a hazard ratio (HR) for relapse of 17.5. HRs for OS and breast cancer-specific survival in PDX+ patients were 21.1 and 39.5, respectively. We report that the ability of a tumor to engraft as a PDX predicts early recurrence by serving as a functional readout of aggressiveness and prospectively identifies the most devastating tumors. This provides new opportunity to develop surrogate assays, such as biomarkers of engraftment, which will extend the clinical feasibility of this finding.

Early detection of pancreatic cancer by liquid biopsy “PANLIPSY”: a french nation-wide study project

BackgroundPancreatic cancer, predominantly characterized by ductal adenocarcinoma (PDAC) accounts for 90% of cases and is the fourth leading cause of cancer-related deaths globally. Its incidence is notably increasing. This poor prognosis is primarily due to late-stage diagnosis (approximately 70% to 80% of patients are diagnosed at an advanced stage), aggressive tumor biology, and low sensitivity to chemotherapy. Consequently, it is crucial to identify and develop a simple, feasible and reproducible blood-based signature (i.e., combination of biomarkers) for early detection of PDAC.MethodsThe PANLIPSY study is a multi-center, non-interventional prospective clinical trial designed to achieve early detection of PDAC with high specificity and sensitivity, using a combinatorial approach in blood samples. These samples are collected from patients with resectable, borderline or locally advanced, and metastatic stage PDAC within the framework of the French Biological and Clinical Database for PDAC cohort (BACAP 2). All partners of the BACAP consortium are eligible to participate. The study will include 215 PDAC patients, plus 25 patients with benign pancreatic conditions from the PAncreatic Disease Cohort of TOuLouse (PACTOL) cohort, and 115 healthy controls, totaling 355 individuals. Circulating biomarkers will be collected in a total volume of 50 mL of blood, divided into one CellSave tube (10 mL), two CELL-FREE DNA BCT® preservative tubes (18 mL), and five EDTA tubes (22 mL in total). Samples preparation will adhere to the guidelines of the European Liquid Biopsy Society (ELBS). A unique feature of the study is the AI-based comparison of these complementary liquid biopsy biomarkers.Main end-points: i) to define a liquid biopsy signature that includes the most relevant circulating biomarkers, ii) to validate the multi-marker panel in an independent cohort of healthy controls and patients, with resectable PDAC, and iii) to establish a unique liquid biopsy biobank for PDAC study.DiscussionThe PANLIPSY study is a unique prospective non-interventional clinical trial that brings together liquid biopsy experts. The aim is to develop a biological signature for the early detection of PDAC based on AI-assisted detection of circulating biomarkers in blood samples (CTCs, ctDNA, EVs, circulating immune system, circulating cell-free nucleosomes, proteins, and microbiota).Trial registrationClinicalTrials.gov Identifier: NCT06128343 / NCT05824403. Registration dates: June 8,2023 and April 21, 2023.

Ethical Expertise for Gene Diagnostics and Gene Therapy Clinical Studies

Purpose of the study: to develop proposals for improving regulatory documentation on ethical expertise (EE) of gene diagnostics and gene therapy clinical studies.Materials and methods. We used general philosophical research methods, including the formal-logical, historical method, comparative method, systematic approach and axiological method. We analyzed 10 international acts, including acts of «soft law», 4 documents adopted at the level of interstate integration entities, 7 domestic normative legal acts, and a number of various doctrinal sources on the topic under consideration. In addition, we analyzed the regulatory documents for ethical committees (EC) acivities, including those from a historical perspective.Results. We formulated the concept of EE, defined the principles and main areas of EE, including the personalized medicine, and suggested the regulatory principles of EE operating.Conclusion. To improve the regulation of EE, the legal status and requirements for the activities of independent ECs should fit the scope of EE, differentially related to the area of a trial (non-interventional trials, clinical trials with a drug treatment); at the national level, independent ECs conducting EE of drug treatmemnt clinical trials should be institutionalized into a single system; to improve the activities of independent ECs in the field of clinical testing, the development of a special normative regulation is required.

Caffeine gum improves 5 km running performance in recreational runners completing parkrun events

PurposeThe purpose of this study was to determine whether caffeine gum improves the performance of recreational runners completing parkruns (weekly, 5 km, mass participant running events).MethodsThirty-six recreational runners (M = 31, F = 5; age 33.7 ± 10.7 y; BMI 23.1 ± 2.4 kg/m2) capable of running 5 km in < 25 min were recruited to a study at the Sheffield Hallam parkrun, UK. Runners were block randomized into one of three double-blind, placebo-controlled, cross-over intervention trials with caffeine gum as the treatment (n = 6 per intervention trial) or into one of three non-intervention trials that ran concurrently with the intervention trials (n = 6 per non-intervention trial). Changes in conditions across different parkruns were adjusted for using data from the non-intervention trials. Runners in the randomized cross-over intervention trials chewed gum supplying 300 mg of caffeine or a placebo gum for 5 min, starting 30 min before each parkrun.ResultsCaffeine gum improved 5 km parkrun performance by a mean of 17.28 s (95% CI 4.19, 30.37; P = 0.01). Adjustment for environmental conditions using data from the non-intervention trials attenuated the statistical significance (P = 0.04). Caffeine gum also decreased RPE by 1.21 (95% CI 0.30, 2.13; P = 0·01) units relative to placebo.ConclusionsA 300 mg dose of caffeine supplied in chewing gum improved the performance of recreational runners completing 5 km parkruns by an average of 17 s.Trial RegistrationThe study was registered at ClinicalTrials.gov: NCT02473575 before recruitment commenced.

Intensive vs Conventional Blood Pressure Control After Thrombectomy in Acute Ischemic Stroke

Endovascular thrombectomy (EVT) is standard treatment for acute ischemic stroke (AIS) due to large-vessel occlusion (LVO), but optimal post-EVT blood pressure (BP) control remains debated. To assess the association of different systolic BP targets following EVT with functional outcomes, mortality, and complications in patients with AIS due to LVO. Systematic review and meta-analysis of databases (PubMed, Embase, Web of Science, Scopus, and Cochrane Library) to September 8, 2023. Inclusion criteria consisted of randomized clinical trials examining post-EVT management of systolic BP in patients with AIS and LVO comparing intensive vs conventional targets. Nonrandomized studies, observational studies, noninterventional trials, meeting abstracts, duplicate studies, studies with overlapping data, and non-English language studies were excluded. Two authors independently applied these criteria through a blinded review, with discrepancies resolved through consensus. The risk of bias in the included studies was assessed using the revised tool for assessing risk of bias in randomized trials. This study adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline. Three authors extracted data regarding study characteristics, baseline patient data, and outcomes of interest. The pooled data were analyzed using a random-effects meta-analysis. Rates of functional independence, 90-day mortality, symptomatic intracranial hemorrhage, and hypotensive events. A total of 4 randomized clinical trials with 1571 initially enrolled patients were included in the analysis. Lower functional independence rates were observed in the intensive control group (relative risk [RR], 0.81 [95% CI, 0.67-0.98]). No significant differences were found in 90-day mortality (RR, 1.18 [95% CI, 0.92-1.52]), symptomatic intracranial hemorrhage (RR, 1.12 [95% CI, 0.75-1.67]), or hypotensive events (RR, 1.80 [95% CI, 0.37-8.76]). There was minimal heterogeneity among the studies included in the functional independence outcome (I2 = 13% and τ2 = 0.003), which was absent among other outcomes (I2 = 0 and τ2 = 0). These findings suggest that intensive post-EVT BP reduction does not yield benefits and may carry risks. While awaiting the results of additional ongoing trials, a conservative BP management strategy after endovascular recanalization is favored in daily practice.

Measuring Quality of Life: Incorporating Objectively Measurable Parameters within the Cross-Sectional Bern Cohort Study 2014 (BeCS-14).

Up until now, the measurement of Quality of Life (QoL) was based on validated subjective rating tools rather than objective measurement. To become more independent of the self-assessment of probands, a way to objectively measure QoL should be found. A monocenter, cross-sectional, observational, non-interventional trial was performed from 2012 to 2014 at Inselspital Bern to evaluate the bio-functional status (BFS), a complex, generic, non-invasive, sex- and age-validated assessment tool, in a wide range of areas. A standardized battery of assessments was performed on 464 females and 166 males, ages 18 to 65 (n = 630). In addition to the survey of the BFS, participants replied-among others-to the validated questionnaire SF-36 for health-related QoL (n = 447, subgroup 1). Since the accepted cut-off value for BFA calculation is age ≥ 35 years, subgroup 2 included 227 subjects (all participants aged ≥ 35 years out of subgroup 1). In order to be able to compare the eight SF-36 subscales to BFS parameters, a comparable score set of single BFS items had to be constructed. Subsequently, we aimed to statistically identify BFS item combinations that best represented each SF-36 subscale. All eight SF-36 subscales were significantly represented by various different combinations of BFS items. A total of 24 single BFS items significantly correlated with SF-36 subscales, of which 15 were objective and nine were subjective. All eight SF-36 subscales were significantly represented by various different combinations of BFS items leading to stronger correlations (range five to nine BFS items), and overall, sex and age did not affect these associations, but in the SF-36 subscales 'bodily pain' (sex) and 'role limitations due to physical health problems' (age in men). To our knowledge, we are the first to correlate a validated set of 34 objective and 9 subjective parameters with subjectively evaluated SF-36 subscales. This first study on the objectifiability of the SF-36 questionnaire demonstrated that questions on quality of life can be answered independently of a subjective assessment by subjects in future scientific studies.

Engaging Underrepresented Patients in Hematology Clinical Trials through the LLS Impact (Influential Medicine Providing Access to Clinical Trials) Research Grant: A Multi-Institutional Effort

Introduction: Despite governmental and industry-sponsored efforts, clinical trial participation among rural residents and racial and ethnic minorities remains low. The NIH Revitalization Act of 1993 directed the NIH to establish guidelines for inclusion of women and minorities in clinical research. In 2015, the Food and Drug Administration launched an action plan to improve the quality of demographic subgroup data collection, identify barriers to enrollment, employ strategies to increase participation, and promote transparency of related data. However subsequent studies (Green et al. Health Aff. March 2022, Kanapuru et al. Blood Advances. March 2022.) showed no improvement in participation of racial minorities, including Blacks and Hispanics since this plan was enacted. Various complex system- and individual-based factors, including lack of clinical trial availability; lack of diversity in the investigator work force; scant patient and provider awareness of clinical trials; lack of trust in the health care system; and issues with access to care-often driven by financial, geographic, or social constraints (Allison et al. Cureus. Apr 2022.), and stringent eligibility criteria are deemed responsible. The Leukemia &amp; Lymphoma Society (LLS) IMPACT (Influential Medicine Providing Access to Clinical Trials) research grant strives to bridge this unrelenting care gap. Methods: The LLS IMPACT program includes a 5-year research grant which was launched in 2021. The IMPACT grants support the establishment of clinical trial networks involving academic cancer centers (“Hubs”) linked to community clinics and oncology centers (“Spokes”). The program's overall goal is to provide patients access to trials through participation at the community sites. Initially, 3 institutional sites were selected to participate. These institutions had unique and tailored strategies to improve engagement of underrepresented patients, including black, indigenous, people of color, Hispanic, Latina/Latino, and people from rural communities in vastly different climates and local cultures. The IMPACT grant expanded to encompass 4 additional sites given the imminent needs and clamor of the hematology clinical trials community (Figure 1A). The catchment areas and strategies employed at each institution are summarized in the table (Figure 1B). Results: At the start of the grant period, focus was on building clinical research infrastructure and opening non-interventional clinical trials to teach personnel about clinical research and create relationships with patients. Other programs such as webinar series, tumor boards, technological advancements, and educational workshops were also established to enhance engagement among physicians, match patients to clinical trials, and to provide clinical trial education to potential patients. One trial that has seen early success is the CHIVE IMPACT trial, a non-interventional registry and biorepository which has enrolled 24 patients at a rural and underserved site as of July 2023. The purpose of CHIVE is to enroll patients who have clonal hematopoiesis (CH) or are at risk of CH and follow prospectively in efforts to understand risk of progression and potential for early intervention. The Universal Protocol is another biorepository trial which has more than tripled its enrollment number at a community site between 2021 and 2022. Of the 63 patients enrolled in 2022, 66% of them identified as a race other than White. As our core goal is to increase access to interventional trials, we hope to bring industry sponsored phase II and phase III studies to underrepresented areas that serve a broad patient population. Lack of financial resources, lack of transportation and distance to trial sites, and residual distrust of the medical community (e.g., legacy of Tuskegee experiments) are barriers the grantees are focused on overcoming to enroll the intended populations into clinical trials. Conclusion: The innovative strategies employed to expand access to clinical trials for underrepresented population at the various institutions through the LLS's IMPACT research grant can be utilized during clinical trials design and implementation phases to improve generalizability of clinical trials in hematologic malignancies. In the third year of this program, 7 participating sites are engaging impactful strategies (Figure 1B) which will be reported at the end of the grant period.

Investigating coping and stigma in people living with HIV through narrative medicine in the Italian multicentre non-interventional study DIAMANTE

Antiretroviral therapy (ART) significantly reduced Human Immunodeficiency Virus (HIV) morbidity and mortality; nevertheless, stigma still characterises the living with this condition. This study explored patients’ coping experience by integrating narrative medicine (NM) in a non-interventional clinical trial. From June 2018 to September 2020 the study involved 18 centres across Italy; enrolled patients were both D/C/F/TAF naïve and previously ART-treated. Narratives were collected at enrolment (V1) and last visit (V4) and then independently analysed by three NM specialist researchers through content analysis. One-hundred and fourteen patients completed both V1 and V4 narratives. Supportive relationships with clinicians and undetectable viral load facilitated coping. Conversely, lack of disclosure of HIV-positive status, HIV metaphors, and unwillingness to narrate the life before the diagnosis indicated internalised stigma. This is the first non-interventional study to include narratives as patient reported outcomes (PROs). Improving HIV awareness and reducing the sense of guilt experienced by patients helps to overcome stigma and foster coping.

Ex vivo drug response profiling for response and outcome prediction in hematologic malignancies: the prospective non-interventional SMARTrial

Ex vivo drug response profiling is a powerful tool to study genotype–drug response associations and is being explored as a tool set for precision medicine in cancer. Here we conducted a prospective non-interventional trial to investigate feasibility of ex vivo drug response profiling for treatment guidance in hematologic malignancies (SMARTrial, NCT03488641). The primary endpoint to provide drug response profiling reports within 7 d was met in 91% of all study participants (N = 80). Secondary endpoint analysis revealed that ex vivo resistance to chemotherapeutic drugs predicted chemotherapy treatment failure in vivo. We confirmed the predictive value of ex vivo response to chemotherapy in a validation cohort of 95 individuals with acute myeloid leukemia treated with daunorubicin and cytarabine. Ex vivo drug response profiles improved ELN-22 risk stratification in individuals with adverse risk. We conclude that ex vivo drug response profiling is clinically feasible and has the potential to predict chemotherapy response in individuals with hematologic malignancies beyond clinically established genetic markers.

Exploring Albumin Functionality Assays: A Pilot Study on Sepsis Evaluation in Intensive Care Medicine.

Human serum albumin (HSA) as the most abundant plasma protein carries multifunctional properties. A major determinant of the efficacy of albumin relies on its potent binding capacity for toxins and pharmaceutical agents. Albumin binding is impaired in pathological conditions, affecting its function as a molecular scavenger. Limited knowledge is available on the functional properties of albumin in critically ill patients with sepsis or septic shock. A prospective, non-interventional clinical trial assessed blood samples from 26 intensive care patients. Albumin-binding capacity (ABiC) was determined by quantifying the unbound fraction of the fluorescent marker, dansyl sarcosine. Electron paramagnetic resonance fatty acid spin-probe evaluated albumin's binding and detoxification efficiencies. Binding efficiency (BE) reflects the strength and amount of bound fatty acids, and detoxification efficiency (DTE) indicates the molecular flexibility of patient albumin. ABiC, BE, and DTE effectively differentiated control patients from those with sepsis or septic shock (AUROC > 0.8). The diagnostic performance of BE showed similarities to procalcitonin. Albumin functionality correlates with parameters for inflammation, hepatic, or renal insufficiency. Albumin-binding function was significantly reduced in critically ill patients with sepsis or septic shock. These findings may help develop patient-specific algorithms for new diagnostic and therapeutic approaches.

#3056 IMPACT OF ALBUMIN BINDING FUNCTION ON PHARMACOKINETICS AND PHARMACODYNAMICS OF FUROSEMIDE

Abstract Background and Aims Albumin binding of furosemide forms the basis for its transport to the kidney and subsequent tubular secretion, which is a prerequisite for the effect of furosemide. Accordingly, high albumin concentrations should result in higher efficacy of furosemide. However, study results on the combination of furosemide in conjunction with albumin and on the efficacy of furosemide in hypoalbuminemia did not confirm this hypothesis. The aim of this study was to determine the efficacy of furosemide not only in relation to concentration, but also to take albumin function into account. Method In a prospective and non-interventional clinical observational trial, blood and urine samples from 50 intensive care patients receiving continuous intravenous furosemide therapy were evaluated. Albumin binding capacity (ABiC) determination allowed conclusions to be drawn about the binding site-specific loading state of albumin by quantifying the unbound fraction of the fluorescent marker dansylsarcosine. In addition, assessment of the total concentration of furosemide in plasma and urine as well as the concentration of free furosemide fraction in plasma was performed by HPLC-MS. The efficacy of furosemide was evaluated by the ratio of urine excretion to fluid intake. Results In patients with an ABiC ≥ 60% free furosemide fraction was significantly lower compared to patients with a lower ABiC (p &amp;lt; 0.001), urinary furosemide concentration was higher (p = 0.136), and a significantly higher proportion of infused furosemide was excreted renally (p = 0.010). ABiC was positively correlated (r = 0.908, p = 0.017) with the increase in urine excretion to fluid input ratio after initiation of furosemide therapy. Conclusion ABiC could serve as a marker for individual response to furosemide and could be used to generate patient-specific therapeutic regimens. In view of the relatively low number of patients in this study, the relationship between furosemide efficacy and albumin function should be investigated in larger studies in the future.

Impact of PD-L1 and KRAS status on the efficacy of nintedanib (NIN) + docetaxel (DOC) following treatment with first-line immune checkpoint inhibitor (ICI) + chemotherapy in patients with adenocarcinoma NSCLC: Analysis of cohort C of the non-interventional VARGADO trial.

e21149 Background: The identification of targetable molecular tumor markers in patients (pts) with NSCLC has increased significantly over the past decades and has resulted in important changes to individual treatment approaches. One such marker is KRASG12C for which a specific treatment is now available following prior systemic therapy. While ICIs ± chemotherapy represent first-line (1L) standard of care, the sequence of subsequent effective therapies still needs to be investigated. Methods: Cohort C of the ongoing, prospective, non-interventional VARGADO study (NCT02392455) is investigating the combination of NIN + DOC as second-line (2L) treatment after prior 1L ICI + chemotherapy in pts with adenocarcinoma NSCLC. This updated analysis of Cohort C focuses on the safety and efficacy of NIN + DOC according to programmed death ligand-1 (PD-L1) and KRAS status. Results: At the cut-off date (December 1, 2022) 219 pts have been enrolled to Cohort C. Median age was 64 years (range: 37–84) and 58.9% (129/219) of pts were men. At baseline, 30.6% (67/219) were ECOG PS 0 and 50.2% (110/219) were ECOG PS 1. 88.1% (193/219) had stage IV disease. Brain metastases were present in 19.2% (42/219) of pts and 88.1% (193/219) had received prior 1L pembrolizumab-based combination therapy. In the overall population, median PFS was 4.5 months (mo; 95% CI: 3.6–5.3, 219 pts) and median OS was 9.6 mo (95% CI: 6.5–11.2, 217 pts) with NIN + DOC. KRAS mutation status has been documented for 119 pts. In KRAS wild-type pts (75/119), median PFS was 3.7 mo (95% CI: 2.6–5.3) and median OS was 7.7 mo (95% CI: 5.2-11.2). In KRAS mutation-positive pts (44/119) median PFS was 5.1 mo (95% CI: 3.4–6.3) and median OS was 6.7 mo (95% CI: 5.3–15.1). In 33 pts with a non-G12C KRAS mutation, median PFS was 5.0 mo (95% CI: 3.4–6.7) and median OS was 6.7 mo (95% CI: 5.3–15.1). ORR was 20.0% (15/75), 25.0% (11/44), 27.3% (9/33) and 18.2% (2/11) in pts with KRAS wild-type, KRAS mutated, non-G12C mutated and G12C mutated status, respectively. The corresponding disease control rates (DCR) were 45.3% (34/75), 47.7% (21/44), 48.5% (16/33) and 45.5% (5/11). PD-L1 status prior to 1L therapy was &lt; 1% in 86 pts and ≥1% in 76 pts and did not impact OS (median 10.6 mo [95% CI: 6.5–15.1] and 10.5 mo [95% CI: 5.7–12.5], respectively) or DCR (51.2% and 51.3%, respectively) with NIN + DOC. The most frequent NIN-related adverse events of any grade in the overall population were diarrhea 34.7% (76/219), nausea 14.2% (31/219), vomiting 8.2% (18/219) and fatigue 7.8% (17/219). Conclusions: NIN + DOC is an effective and safe 2L treatment option after prior 1L ICI + chemotherapy for NSCLC adenocarcinoma pts independent of PD-L1 and KRAS status. Clinical trial information: NCT02392455 .