Non-interventional Study Research Articles

Pelvic parameters as prognostic factors of radiographic progression in classical Ankylosing Spondylitis: A prospective follow-up data.

Radiographic progression in Ankylosing spondylitis (AS) is driven by mechanical strain. A well-balanced spine provides a favorable weight distribution across the entheses. Pelvic parameters are useful in assessing the shape of the spine. The present study aimed to prospectively investigate the predictive value of pelvic parameters for radiographic progression in AS. This non-interventional, observational, and prospective study enrolled AS patients fulfilling the modified New York criteria (mNY) currently under follow-up in the MARS (MARmara Spondyloarthritis) outpatient clinics. The primary objective was to investigate the relationship between the baseline pelvic parameters and radiographic progression in the spine. Two trained radiologists (EB, OB) independently assessed the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS). An orthopedic surgeon (AHA) and a radiologist (EB) derived the pelvic parameters. Patients with no bridging or bamboo spine were included in the final analysis. Risk assessment for radiographic progression, defined as a two-unit increase in mSASSS or developing a new syndesmophyte every two years, was done using uni- and multivariate logistic regression analyses. Radiographs of 69 AS patients were analyzed. The median (IQR 25-75) prospective follow-up was 47.7 (34.6-52.8) months. Only 33.3% (23/69) had radiographic progression. The pelvic tilt (PT) was lower in patients with radiographic progression (p = 0.037) and each degree of decrease in PT provided a 9% increase in risk for radiographic progression. Male patients were 7.5 times more likely to progress. Pelvic parameters provide a prognostic insight into the radiographic progression in AS. Our observations may aid in selecting patient-specific interventions in addition to anti-inflammatory treatments.

P-202 Impact of multinucleation at the two-cell stage on pregnancy outcomes: a day 3 vs. day 5 transfer analysis

Abstract Study question Does multinucleation at the two-cell stage significantly affect pregnancy outcomes, and how does it differ between day 3 and day 5 embryo transfers? Summary answer Multinucleation at the two-cell stage has a negative effect on pregnancy outcomes in day 3 embryo transfers, but not in day 5 transfers. What is known already Time-lapse imaging provides a valuable tool to study multinucleation in human embryos, although the impact on development and pregnancy remains debated. Literature shows conflicting findings, with most studies associating multinucleation in the early stage embryo with altered developmental potential and decreased pregnancy outcomes. However, other studies suggest a positive correlation, indicating that multinucleated embryos can progress successfully through development and lead to positive pregnancy outcomes. These discrepancies underscore the complexity of and highlight the need for understanding the implications of multinucleation in the context of human embryo development and pregnancy. Study design, size, duration A non-interventional retrospective study on multinucleation was performed on all cycles cultured in a time-lapse incubator in a Dutch fertility clinic between November 2021 and July 2023. In total, 915 embryos (out of 406 cycles) were analyzed and 406 resulting transfers (both fresh and frozen-thawed) were included in this study. Participants/materials, setting, methods Fresh single-embryo transfer was performed on day 3 (for cycles with less than 4 2PN-embryos) or day 5 (for cycles with 4 or more 2PN-embryos). Embryos were vitrified on day 5 or 6 (at least B3BB Gardner score). Nucleation status at the two cell stage was annotated for all transferred and vitrified embryos. Ongoing pregnancies were compared for embryos with or without multinucleation (mononucleation) at the two cell stage. Main results and the role of chance Multinucleation at the two cell stage was observed in 40% (n = 366/915) of all embryos. Multinucleated embryos transferred on day 3 showed a decreased ongoing pregnancy result (17%; n = 9/54) compared to the mononucleated day 3 transfers (29%; n = 24/83). For day 5 transfers, no difference in ongoing pregnancy rates was observed between the multinucleated (37%; n = 37/101) and mononucleated (37%; n = 62/168) groups. These results indicate that development to the blastocyst stage negates any possible negative effect multinucleation can have on cleavage stage embryos. Limitations, reasons for caution A mayor limitation to this study is the small sample size of specifically day 3 transfers. Patients with more than one transfer were allowed to be included. Confounding factors were not assessed. Additionally, different types of multinucleation might result in different clinical effects. Wider implications of the findings Although additional research is needed, these results suggest that assessment of nuclear status at the two-cell stage is important for day 3 transfer strategies, but less so for day 5 blastocyst transfers. Trial registration number Not applicable

P-705 Telomere length of white blood cells is a non-invasive marker of reproductive aging in women

Abstract Study question Can leukocyte telomere length be a marker of ovarian decline? Summary answer The significant correlation found between leukocyte and cumulus cell telomere lengths supports the use of leukocyte telomere length (TL) as a marker of ovarian aging. What is known already The telomere-based theory of reproductive aging proposes that age-related ovarian dysfunction is a consequence of progressive telomere shortening from fetal oogenesis to the adult ovary, compromising genome stability and proper chromosome segregation. Telomere length in cumulus cells (CCTL) is known to be a biomarker of oocyte and embryo quality, but its assessment is not practical. Hence, we previously proposed leukocyte telomere length (LTL) as an alternative to directly measuring telomere length in follicular cells, but so far it has only been assessed in samples of moderate size and homogeneous populations without consistent results. Study design, size, duration This prospective, non-interventional cohort study involved 300 women aged 18 to 46 years undergoing controlled ovarian stimulation over a 24-month period. The cohort included 169 egg donors and 131 IVF patients. Oocyte retrieval was performed 36 hours after maturation induction, with cumulus cells collected during oocyte stripping and blood samples taken via peripheral venous access. Participants/materials, setting, methods Genomic DNA was isolated from leukocytes and cumulus cells of all subjects for TL measurements. Relative TL was determined using a SYBR-Green quantitative real-time PCR protocol. A Taqman assay for the multicopy gene Alu was used to normalize the measurements. A Pearson’s correlation test was used to analyze the correlation between CCTL and LTL, as well as between TL and age, antral follicle count, Anti-Müllerian hormone, and number of mature oocytes retrieved. Main results and the role of chance Mean age of the subjects was 30.70±7.61 years. Anti-Müllerian hormone (AMH) mean level was 2.60±1.87 ng/ml, antral follicle count (AFC) was 17.8±7.4 and the number of mature oocytes was 14.3±9.3. A significant correlation was observed between CCTL and LTL (R = 0.6, p-value=2.2E-16). Notably, the relationship between leukocyte and cumulus cell telomere lengths was stronger in the 97 participants over 35 years (R = 0.67, p-value=1.55E-13), especially those between 39 to 46 years (R = 0.70, p-value=1.19E-12). Telomere length was inversely correlated with age in both leukocytes and cumulus cells (R=-0.23, p-value=6.98E-05; R=-0.4, p-value=2.38E-05), meaning the older the subject, the shorter the telomeres in both cells. Furthermore, longer telomeres in leukocytes and cumulus cells were significantly correlated with higher AFC (R = 0.20, p-value=0.0006; R = 0.25, p-value=1.83E-05), and more mature oocytes retrieved (R = 0.16, p-value=0.0043; R = 0.27, p-value=2.83E-06). However, we did not find any association between AMH levels and LTL or CCTL (R = 0.07, p-value=0.2666; R = 0.07, p-value=0.2747). Limitations, reasons for caution The method used to measure the average telomere length from pooled leukocyte samples may not reflect individual cell variability. Additionally, it allows for relative but not absolute telomere length comparisons. Wider implications of the findings This study is the first to demonstrate in a large and heterogeneous population that LTL could be a viable marker for ovarian aging by reflecting follicular cell telomere length. This finding may provide a valuable tool for assessing and monitoring the reproductive health of IVF patients. Trial registration number Not applicable

Treatment pattern among patients with relapsed/refractory multiple myeloma (RRMM) who had received pomalidomide-based regimens in Taiwan

ABSTRACT Background/purpose The treatment landscape of relapsed/refractory multiple myeloma (RRMM) is rapidly evolving in Taiwan. The present study aimed to assess the treatment patterns among RRMM patients in Taiwan. Methods This retrospective, chart review-based, non-interventional study collected data on RRMM patients (≥20 years old) receiving pomalidomide-based treatment between January 2017 and December 2020 across five sites in Taiwan. Results Median age of the study population was 65.6 years. Approximately 75% patients received a doublet regimen and 25% were on a triplet regimen. Disease progression was the most common cause for switching to pomalidomide-based treatments in doublet (71.2%) and triplet (58.3%) groups. Patients in doublet and triplet groups (>80%) received 4 mg pomalidomide as a starting dose. Overall response rate (ORR: 31.5% and 45.8%) and median progression-free survival (PFS: 4.7 and 6.8 months) were reported in the doublet and triplet regimen. Doublet regimen was discontinued mainly due to disease progression or death (78.1%); however, triplet regimen patients mainly terminated their treatment due to reimbursement limitations (29.2%). Healthcare resource utilization (HRU) was comparable between doublet and triplet groups. Conclusion In Taiwan, half of RRMM patients received pomalidomide-based triplet regimens. Triplet regimens showed a trend towards better outcomes with longer PFS and higher response rates compared to doublets. Notably, the duration of triplet use is influenced by reimbursement limitations. This study provides insight into RRMM treatment patterns in Taiwan and the findings suggest that triplet regimens may be a better alternative than doublet regimens.

Proton therapy for head and neck cancer therapy: A real-world data case study from Bulgaria

Head and neck cancers (HNC) are one of the most severe types of cancer in Europe, accounting for almost 4.5% of all cancer types, according to GLOBOCAN. The incidence is geographically variable, with higher rates observed in Eastern and Southern Europe than in Northern and Western Europe. Proton and photon therapies are both available treatment approaches for head and neck cancer, as each has its own unique advantages, characteristics, and considerations. Proton therapy is the newest one and is considered safer among both. The current study aims to analyse the available data for patients with head and neck cancer treated with proton therapy in Bulgaria based on real-world data generated through AI-based patient registries and the current availability of strategic policy documents ensuring the affordability of proton therapy on a national level. We wanted to explore the feasibility of building a national proton therapy centre based on available patients’ information and strategic policy documents. We conducted a 3-year (2020–2022) combined non-interventional retrospective database study on head and neck cancer using secondary use of real-world data from dynamic patient registries and desktop analysis of strategic policy documents for capacity and financial affordability for proton therapy in Bulgaria. The results show that Bulgaria has a strategic policy document that focuses on the need and funding possibilities for establishing this treatment within the country. However, the country lacks the political will to ensure appropriate funding for it. Building a national proton centre is a feasible investment but needs additional detailed budget impact analysis.

Treatment with the SQ tree sublingual immunotherapy tablet is safe and well tolerated in real-life.

The SQ tree sublingual immunotherapy (SLIT)-tablet is authorised for treatment of allergic rhinoconjunctivitis with or without asthma in trees of the birch homologous group in 21 European countries. The primary objective of this study was to explore the safety in real-life. In a prospective, non-interventional post-authorisation safety study (EUPAS31470), adverse events (AEs) and adverse drug reactions (ADRs) at first administration and follow-up visits, symptoms, medication use, and pollen food syndrome were recorded by physicians in 6 European countries during the first 4-6months of treatment. ADRs with the SQ tree SLIT-tablet were reported in 57.7% of 1069 total patients (median age 36.0years, 53.7% female) during the entire observation period (severity, mild-to-moderate: 70.1%, severe: 4.7%, serious: 0.7%) and in 45.9% after first administration. ADRs were not increased with pollen exposure at first administration. With coadministration of the SQ tree and grass SLIT-tablet AEs were reported in 73.8% of patients and in 52.8% with the SQ tree SLIT-tabletalone. Nasal and eye symptoms improved in 86.9% and 80.9% of patients and use of symptomatic medication in 76.0%. PFS with symptoms was reported in 43.0% of patients at baseline and in 4.3% at the individual last visit. The results of this non-interventional safety study with the SQ tree SLIT-tablet confirm the safety profile from placebo-controlled clinical trials and support effectiveness in real-life according to the published efficacy data. Safety was not impaired by pollen exposure at first administration or co-administration with other SLIT-tablets.

Probiotics plus vitamin D in irritable bowel syndrome: a prospective multicentric non-interventional study.

Patients with irritable bowel syndrome (IBS) experience recurrent symptoms and anxiety disorders that significantly impact their quality of life (QoL). The aim of the study was to assess in daily practice the benefit of the combination of three probiotic strains (Lactobacillus plantarum CETC 7484 and CETC 7485; Pediococcus acidilactici CECT 7483) plus vitamin D in patients with diarrhea-predominant IBS (IBS-D) or IBS with mixed bowel movements (IBS-M). This was a prospective, multicenter, non-interventional study in adult patients with IBS-D or IBS-M (Rome IV criteria) followed by private-practice gastroenterologists. Patients received daily one sachet of a combination of probiotics (3×109 CFU) and vitamin D (10 μg) for 42 days. The primary endpoint was the responder rate at D42 (≥50% and/or ≥100-point decrease of IBS-Severity Scoring System; IBS-SSS). Gut-related anxiety was measured with the Visceral Sensitivity Index (VSI). The full analysis set population included 246 patients (mean age, 51.2±15.4 years; women, 73.2%; IBS-D, 56.1%; IBS-M, 43.9%). At D42, among the 89 patients with evaluable data, the responder rate was 62.9% with a mean decrease of IBS-SSS of 146.6±125.9 (P<0.0001). Changes of IBS-SSS were significantly correlated with changes of IBS-QoL (r=-0.78; P<0.0001), HAD-anxiety (r=0.46; P<0.0001), HAD-depression (r=0.61; P<0.001) and VSI (r=0.74; P<0.0001). These real-life results are in line with a previous randomized clinical trial demonstrating the benefits of this combination in IBS-D and IBS-M. Symptom relief was associated with improvement of IBS-QoL, anxiety, depression and specifically gut-related anxiety.

Results of a 12-Week Open-Label, Non-Interventional Study of the Efficacy and Safety of Olokizumab Therapy in Patients with Rheumatoid Arthritis after Switching from Anti-B-Cell Therapy during the SARS-CoV-2 Pandemic.

The purpose of the study was to evaluate the efficacy and safety of the drug Artlegia® (olokizumab), solution for subcutaneous injection, 160 mg/ml-0.4 ml, manufactured by R-Pharm JSC, Russia) for the treatment of patients with rheumatoid arthritis in real clinical practice after switching with rituximab during the COVID-19 pandemic. The study included 14 patients with a confirmed diagnosis of rheumatoid arthritis (RA), who were previously on rituximab therapy at a dose of 1000-500 mg twice with an interval of 2 weeks, who received at least one course of therapy with this drug. As RA worsened, patients were switched to olokizumab against the background of standard DMARDs. On weeks 0, 4, 8, and 12 after the switch, the severity of pain was assessed on the VAS scale, the number of tender and swollen joints (TJC28 and SJC28), the level of acute-phase inflammation markers, the DAS28 (disease activity score), ESR, CRP, CDAI (clinical activity index), and the functional state index HAQ (Health Assessment Questionnaire) were determined, as well as the safety profile of therapy was assessed. Data analysis was performed using median values (Me) were used for data analysis. A significant decrease in TJC28 was detected after 8 and 12 weeks of treatment with olokizumab (Artlegia®) (Me baseline = 10, Me 8 weeks = 4, Me 12 weeks = 4, p < 0.05) and a decrease in TSC28 was detected after 4, 8, and 12 weeks of treatment (Me baseline = 9, Me 4 weeks = 3.5, Me 8 weeks = 2.5, Me 12 weeks = 2.0, p < 0.05). Laboratory markers of inflammation showed a decrease in CRP and ESR levels after 4 weeks of treatment (CRP: Me4 weeks = 21, Me4 weeks = 1, p < 0.05, ESR: Mesno = 31, Me4 weeks = 7, p < 0.05). Positive dynamics persisted on 8 and 12 weeks (CRP: Me 8 weeks = 1, Me 12 weeks = 0; ESR: Me 8 weeks = 4, Me 12 weeks = 5). The level of CRP by week 4 became within the normal range, regardless of the initial values. All activity indices improved from week 4 in each evaluation period compared to baseline: DAS28-ESR: Me baseline = 5.52, Me 4 weeks = 3.59, Me 8 weeks = 3.33, Me 12 weeks = 3.22, p < 0.05; DAS28CRP: Me baseline = 5.39, Me 4 weeks = 3.71, Me 8 weeks = 3.35, Me 12 weeks = 3.45, p < 0.05; CDAI: Me baseline = 28.5, Me 4 weeks = 18.0, Me 8 weeks = 16.5, Me 12 weeks = 16.0, p < 0.05. All patients showed a reduction in pain (VAS scale) by week 8. The functional status of patients, according to the HAQ index, showed a significant decrease only by week 12 of the study: Me baseline = 1.62, Me 12 weeks = 1.31, p < 0.05. The study found that switching from rituximab to olokizumab was effective and safe during the COVID-19 pandemic.

Final Analysis of a Noninterventional Study on Cabozantinib in Patients With Advanced Renal Cell Carcinoma After Prior Checkpoint Inhibitor Therapy of the German Interdisciplinary Working Group on Renal Tumors (IAG-N)

BackgroundEfficacy of treatment after failure of check point inhibitors (ICI) therapy remains ill-defined in metastatic renal cell carcinoma (mRCC). ObjectiveTo evaluate the safety and effectiveness of cabozantinib after failure of ICI-based therapies. Design, setting and participantsPatients with mRCC who concluded cabozantinib treatment directly after an ICI-based therapy were eligible. Data was collected retrospectively from participating sites in Germany. InterventionsCabozantinib was administered as a standard of care. Outcome measurements and statistical analysisAdverse events (AE) were reported according to CTCAE v5.0. Objective response rate according to RECIST 1.1 and Progression Free Survival (PFS) were collected from medical records. Descriptive statistics and Kaplan-Meyer-plots were utilized. Results and limitationsAbout 56 eligible patients (71.4% male) with median age of 66 years and clear cell histology in 66.1% (n = 37) were analyzed. 87.5% (n = 49) had ≥ 2 previous lines. IMDC risk was intermediate or poor in 17 patients (30.4%) and missing in 66.1%. 20 patients (35.7%) started with 60 mg. 55.4% (n = 31) required dose reductions, 26.8% (n = 15) treatment delays and 1.8% (n = 1) treatment discontinuation. Partial response was reported in 10.7% (n = 6), stable and progressive disease were reported in 19.6% (n = 11) and in 12.5% (n = 7). 32 patients were not evaluable (57.1%). Median treatment duration was 6.1 months. Treatment related AE were reported in 76.8% (n = 43) and 19.6% (n = 11) had grade 3-5. Fatigue (26.8%), diarrhea (26.8%) and hand-foot-syndrome (25.0%) were the 3 most frequent AEs of any grade and causality. SAE were reported in 21.4% (n = 12), 2 were fatal. Major limitation was the retrospective data capture in our study. ConclusionsCabozantinib followed directly after ICI-based therapy was safe and feasible. No new safety signals were reported. A lower starting dose was frequently utilized in this real-world cohort, which was associated with a favorable tolerability profile. Our data supports the use of cabozantinib after ICI treatment.

Role of fibroblast growth factor-23 as an early marker of metabolic bone disease of prematurity

PurposeMetabolic bone disease of prematurity (MBDP) remains a significant cause of morbidity in extremely premature newborns. In high-risk patients, suspected diagnosis and subsequent treatment modifications, with limitations in terms of sensitivity and specificity, rely on low phosphorus levels and/or high levels of alkaline phosphatase (ALP). We investigated the potential of fibroblast growth factor-23 (FGF23) as an early marker for MBDP when measured at 3–4 weeks of life in at-risk patients.MethodsA single-center prospective observational non-interventional study including preterm newborns of both sexes, with a gestational age of less than 32 weeks and/or a birth weight of less than 1500 g. In the standard biochemical screening for MBDP performed between 3 and 4 weeks of life within a nutritional profile, the determination of FGF23 was included along with other clinical and metabolic studies. The study was conducted at Marqués de Valdecilla University Hospital in Santander, Spain, from April 2020 to March 2021. Participants provided informed consent. Biochemical analyses were conducted using various platforms, and follow-up evaluations were performed at the discretion of neonatologists. Patients at high risk for MBDP received modifications in treatment accordingly. The sample was descriptively analyzed, presenting measures of central tendency and dispersion for continuous variables, and absolute numbers/percentages for categorical ones. Tests used included t-tests, Mann‒Whitney U tests, chi-square tests, logistic regressions, Pearson correlation, and ROC curve analysis (IBM SPSS Statistics version 19). Significance level: P < 0.05.ResultsIn the study involving 25 at-risk premature newborns, it was found that 20% (n = 5) were diagnosed with MBDP. Three of these patients (60%) were identified as high-risk based on standard biochemical evaluation at 3–4 weeks of age, while the other two patients (40%) were diagnosed in subsequent weeks. However, in all 5 patients, measurement of FGF23 levels would allow for early identification and optimization of treatment before other markers become altered. Low levels of FGF23 at 3–4 weeks, even with normal phosphorus and ALP levels, indicate the need for modifications in nutritional supplementation.ConclusionsMBDP remains a significant concern in extremely premature newborns. Current diagnostic methods rely on limited biochemical markers. Early detection of low FGF23 levels enables timely interventions, potentially averting demineralization.

Certolizumab Pegol for the Treatment of Plaque Psoriasis in Routine Clinical Practice: One-Year Results from the CIMREAL Study.

Certolizumab pegol (CZP) is an anti-tumor necrosis factor alpha (TNFα) approved for the treatment of moderate to severe plaque psoriasis (PSO). However, data on its real-world use is currently limited. The objective of this study was to describe the 1-year real-world effectiveness of CZP, its impact on health-related quality of life (HRQoL), and safety outcomes in patients with moderate to severe PSO in multi-country settings. CIMREAL, a prospective, noninterventional study, was conducted across Europe and Canada from August 2019 to December 2022. Patients were followed for 1-year, receivingCZP 400mg initial doses at weeks 0, 2, and 4, followed byCZP 200mg every 2weeks (Q2W) or CZP 400mg Q2W maintenance dosing. Effectiveness was assessed using the Psoriasis Area and Severity Index (PASI) and Dermatology Life Quality Index (DLQI). Safety was also evaluated. Overall, 399 patients with moderate to severe PSO were included. Of these, 93.7% (374/399) and 77.9% (311/399) completed months 3 and 12, respectively. Mean age (± standard deviation) was 42.9 ± 13.5yearsand body mass index was 28.5 ± 6.8kg/m2, with the majority of patients being female (68.2%). At 12months, CZP showed substantial effectiveness, achieving PASI 75 and PASI 90 response rates (≥ 75% and ≥ 90% improvement from baseline, respectively) of 77% and 56.5%, respectively. Patients with PASI score of ≤ 3 and ≤ 2 experienced improvement from 3months (49.8% and 41.1%, respectively) to 12months (82.0% and 75.3%, respectively). HRQoL considerably improved, with mean DLQI scores decreasing from 12.4 to 2.3 after 12months of treatment, and the proportion of patients with DLQI 0/1 increased from 28.6% at 3months to 59.4% at 12months. The 1-year probability of persistence was approximately 85%. Overall, 30.6% of the patients experienced any adverse events and 9.3% had serious adverse events. In routine clinical practice, CZP exhibited consistent effectiveness, positively impacting both skin psoriasis activity and HRQoL. The 1-year persistence of CZP was high, and no new safety signals were identified. ClinicalTrials.gov Identifier: NCT04053881 https://www. gov/study/NCT04053881 .

Utilization of MANAGE-PD Tool in a Real-World Setting in Germany: A Cross-Sectional Study.

MANAGE-PD is a validated, web-based tool to assist physicians in identifying patients with Parkinson's disease (PD) whose symptoms are inadequately controlled by oral medication. Also, a modified patient version of MANAGE-PD (Parkinson Check) is available in Germany. However, prospective research into the clinical utility of MANAGE-PD is lacking. This non-interventional study aimed to assess the real-world clinical utility of the MANAGE-PD and Parkinson Check in PD patients attending a single visit at specialist clinics and neurologist practices in Germany in 2022. Participants' disease control was rated by the physicians using their own judgment, and by completing the MANAGE-PD, and by the patients completing the Parkinson Check. Concordance was calculated between the unassisted physician's assessment and the outcome of MANAGE-PD, as well as the Parkinson Check. A total of 278 patients from 19 sites were included in the analyses, of whom 160 patients (57.6%) were assigned to the same category of disease control by physicians' judgment and the MANAGE-PD. Concordance was higher in patients treated in specialist clinics (63.9%) than in neurologist practices (43.7%). Concordance between physicians' and patients' responses was high (>80%) for each question in the Parkinson Check. MANAGE-PD proved to be especially valuable for general neurologists in identifying patients who should be referred to specialist clinics. The Parkinson Check self-assessment generated promising outcomes that merit its more widespread use.

Aging-Related CYP3A Functional Changes in Chinese Older Patients: New Findings from Model-Based Assessment of Amlodipine.

Aging-related alterations in hepatic enzyme activity, particularly of the CYP3A, significantly impact drug efficacy and safety in older adults, making it essential to understand how aging affects CYP function for optimal drug therapy. The exogenous probe substrate method, a minimally invasive approach to assess liver metabolic enzyme activity in vivo, is effective in studying these changes. Amlodipine being extensively metabolized (> 90%) in the liver, primarily via cytochrome P450 enzyme CYP3A was selected as a probe to investigate and quantify the factors affecting the aging-related changes of CYP3A in the Chinese older population. Amlodipine concentration data were collected from an ongoing noninterventional clinical study conducted at Peking University Third Hospital. A physiologically-based pharmacokinetic modeling approach, grounded in population pharmacokinetic (PPK) analysis, was employed to physiologically quantify the aging-related changes in CYP3A function. A total of 132 amlodipine concentrations from 69 patients were obtained from the clinical study. PPK analysis shows that frailty phenotype but not age is a significant influence and frail patients have 37% greater plasma amlodipine exposure than nonfrail patients. This difference in CYP3A function may be attributed to a 63.2% lower CYP3A relative abundance in the frail patients, compared with that in the nonfrail patients. In the context of dose selection for older adults, focusing on frailty rather than chronological age should be recognized as a more relevant approach, because frailty might more accurately reflect the individual's biological age. Our study suggested a need to shift the research focus from chronological age to biological age.

Real-world usage and effectiveness of recombinant factor VIII/factor IX Fc in hemophilia A/B: final data from the 24-month, prospective, noninterventional PREVENT study in Germany

BackgroundReal-world experience with efmoroctocog alfa (a recombinant factor [F]VIII Fc fusion protein [rFVIIIFc]) and eftrenonacog alfa (a recombinant factor IX Fc fusion protein [rFIXFc]) is needed to bridge evidence gaps. ObjectivesTo describe rFVIIIFc/rFIXFc usage and effectiveness over a 24-month prospective period. MethodsPREVENT (NCT03055611), a noninterventional study across 25 German hemophilia treatment centers, enrolled previously treated persons with hemophilia A and B (all ages/severities) on individualized rFVIIIFc/rFIXFc prophylaxis before/at enrollment. Primary endpoints included annualized bleeding rate (ABR), injection frequency (IF), and factor consumption (FC). Additionally, up to 12 months of retrospective FVIII/FIX data were collected. Physician and patient satisfaction, and safety outcomes were also assessed. ResultsOverall, 150 patients received ≥1 rFVIIIFc dose and 47 patients received ≥1 rFIXFc dose, with median prospective follow-up of 20.6 and 21.0 months, respectively. rFVIIIFc/rFIXFc demonstrated low median ABR (0.5/1.7), annualized IF (121.8/52.2 injections/y), and FC (4611.7/2423.9 IU/kg) in line with product labels. Compared with previous FVIII/FIX, there was a 56.0% reduction in ABR for rFVIIIFc (rate ratio, 0.44; 95% CI, 0.31-0.64), with no change for rFIXFc (rate ratio, 0.93; 95% CI, 0.66-1.31); rFVIIIFc/rFIXFc reduced annualized IF (rFVIIIFc, mean difference, −31.7; 95% CI, −40.3 to −23.1; rFIXFc, mean difference, −37.3; 95% CI, −46.9 to −27.8), while FC remained stable (rFVIIIFc, +374.1; 95% CI, +46.8 to +701.3; rFIXFc, +503.9; 95% CI, +95.4 to +912.4). Most physicians and patients were satisfied or highly satisfied with rFVIIIFc/rFIXFc. rFVIIIFc/rFIXFc were well tolerated, with no inhibitor development or treatment-related serious adverse events. ConclusionReal-world PREVENT data complement phase 3 trials and show that individualized rFVIIIFc/rFIXFc prophylaxis provided stable bleed protection with low IF and maintained FC. Compared with previous FVIII, ABR was considerably reduced with rFVIIIFc, with stable annualized FC. For rFIXFc, bleed protection was maintained vs previous FIX while reducing annualized IF.

Non-interventional observational retrospective-prospective study of health-related quality of life (EuroQoL) in patients with vasculitis associated with antineutrophil cytoplasmic antibodies undergoing treatment with rituximab

Non-interventional observational retrospective-prospective study of health-related quality of life (EuroQoL) in patients with vasculitis associated with antineutrophil cytoplasmic antibodies undergoing treatment with rituximab

Emergency physicians' and nurses' perception on the adequacy of emergency calls for nursing home residents: a non-interventional prospective study.

A considerable percentage of daily emergency calls are for nursing home residents. With the ageing of the overall European population, an increase in emergency calls and interventions in nursing homes (NH) is to be expected. A proportion of these interventions and hospital transfers may be preventable and could be considered as inappropriate by prehospital emergency medical personnel. The study aimed to understand Belgian emergency physicians' and emergency nurses' perspectives on emergency calls and interventions in NHs and investigate factors contributing to their perception of inappropriateness. An exploratory non-interventional prospective study was conducted in Belgium among emergency physicians and emergency nurses, currently working in prehospital emergency medicine. Electronic questionnaires were sent out in September, October and November 2023. Descriptive statistics were used to analyze the overall results, as well as to compare the answers between emergency physicians and emergency nurses about certain topics. A total of 114 emergency physicians and 78 nurses responded to the survey. The mean age was 38 years with a mean working experience of 10 years in prehospital healthcare. Nursing home staff were perceived as understaffed and lacking in competence, with an impact on patient care especially during nights and weekends. General practitioners were perceived as insufficiently involved in the patient's care, as well as often unavailable in times of need, leading to activation of Emergency Medical Services (EMS) and transfers of nursing home residents to the Emergency Department (ED). Advance directives were almost never available at EMS interventions and transfers were often not in accordance with the patient's wishes. Palliative care and pain treatment were perceived as insufficient. Emergency physicians and nurses felt mostly disappointed and frustrated. Additionally, differences in perception were noted between emergency physicians and nurses regarding certain topics. Emergency nurses were more convinced that the nursing home physician should be available 24/7 and that transfers could be avoided if nursing home staff had more authority regarding medical interventions. Emergency nurses were also more under the impression that pain management was inadequate, and emergency physicians were more afraid of the medical implications of doing too little during interventions than emergency nurses. Suggestions to reduce the number of EMS interventions were more general practitioner involvement (82%), better nursing home staff education/competences (77%), more nursing home staff (67%), mobile palliative care support teams (65%) and mobile geriatric nursing intervention teams (52%). EMS interventions in nursing homes were almost never seen as necessary or indicated by emergency physicians and nurses, with the appropriate EMS level almost never being activated. The following key issues were found: shortages in numbers and competence of nursing home staff, insufficient primary care due to the unavailability of the general practitioner as well as a lack of involvement in patient care, and an absence of readily available advance directives. General practitioners should be more involved in the decision to call the Emergency Medical Services (EMS) and to transfer nursing home residents to the Emergency Department. Healthcare workers should strive for vigilance regarding the patients' wishes. The emotional burden of deciding on an avoidable hospital admission of nursing home residents, perhaps out of fear for medico-legal consequences if doing too little, leaves the emergency physicians and nurses frustrated and disappointed. Improvements in nursing home staffing, more acute and chronic general practitioner consultations, and mobile geriatric and palliative care support teams are potential solutions. Further research should focus on the structural improvement of the above-mentioned shortcomings.

CO65 Overall Survival in Metastatic NSCLC in HMO From Colombia: A Non-Interventional Study

CO65 Overall Survival in Metastatic NSCLC in HMO From Colombia: A Non-Interventional Study

PCR150 Burden of Invasive Meningococcal Disease in Survivors and Their Caregivers in the United States: A Cross-Sectional Non-Interventional Mixed Methods Study

PCR150 Burden of Invasive Meningococcal Disease in Survivors and Their Caregivers in the United States: A Cross-Sectional Non-Interventional Mixed Methods Study

Usefulness of biomarkers to predict prognosis after heart transplant

Introduction and objectivesHeart transplant (HT) represents a major physiological stress, resulting in elevated levels of analytical biomarkers. This study aimed to determine whether changes in biomarker levels after HT can identify patients with a poor prognosis. MethodsA prospective longitudinal noninterventional study was conducted in 149 consecutive patients undergoing HT from July 2017 to July 2023. Biomarkers were assessed before HT and at 6, 24, 48, 72, and 96hours after HT. The biomarkers analyzed were high-sensitivity troponin T, N-terminal pro-B-type natriuretic peptide (NT-proBNP), creatinine, and lactic acid. The primary outcome was a composite of death and severe primary graft failure (PGF). ResultsNT-proBNP and troponin levels remained highly elevated throughout the period and stabilized from the first 24hours post-HT. Lactate levels stabilized after the first 24hours, and creatinine from the second day onward. Exitus occurred in 23 (15%) of the patients, and severe PGF in 26 (17%). All biomarkers were significantly associated with the incidence of the combined event (P <.0001). Receiver operating characteristic curve analysis at 24hours showed significant areas under the curve (P=.0001). The greatest discriminatory power was observed for the NT-proBNP curve. A value of 10 000 pg/mL had a sensitivity of 90% and specificity of 80%. ConclusionsA significant elevation of post-HT analytical biomarkers was associated with mortality and/or severe PGF. Among the biomarkers analyzed, NT-proBNP was the most accurate in classifying patients.

Therapeutic drug monitoring of linezolid and exploring optimal regimens and a toxicity-related nomogram in elderly patients: a multicentre, prospective, non-interventional study.

The concentrations of linezolid, its optimal regimen and the associated side effects in elderly patients remain unclear. In this multicentre, prospective study, elderly patients receiving linezolid at four tertiary hospitals in Beijing between May 2021 and December 2022 were included. Linezolid concentrations and haematological toxicity were monitored dynamically. Risk factors for linezolid overexposure and moderate-to-severe linezolid-induced thrombocytopenia (M/S LIT) were analysed, and a predictive model of M/S LIT was developed. A total of 860 linezolid concentrations were measured in 313 patients. The median trough concentrations of linezolid were 24.4 (15.3, 35.8) mg/L at 36-72 h and 26.1 (17.0, 38.1) mg/L at 5-10 days (P = 0.132). Severe linezolid exposure was independently associated with age, estimated glomerular filtration rate (eGFR) and the worst SOFA score (SOFA1), and we further recommended dose regimens for elderly patients based on these findings. The incidences of linezolid-induced thrombocytopenia(LIT) and M/S LIT were 73.5% and 47.6%, respectively. M/S LIT was independently correlated with treatment duration, average trough concentration (TDMa), baseline platelet count, eGFR and baseline SOFA score (SOFA0). The developed nomogram predicted M/S LIT with an area under the curve of 0.767 (95% CI 0.715-0.820), a sensitivity of 71.1% and a specificity of 73.2%. Linezolid trough concentrations increased dramatically in the elderly, by about 10 mg/L in patients aged 65-80 years, followed by a further increase of 10 mg/L for every 10 years of age. Therapeutic drug monitoring is recommended in elderly patients receiving linezolid. The developed nomogram may predict M/S LIT and guide dosage adjustments of linezolid. Clinical trial registration number: ChiCTR2100045707.