Design Of Future Trials Research Articles

Validation of a biomarker-based mortality score for cardiogenic shock patients: Comparison with a clinical risk score.

Cardiogenic shock (CS) is the deadliest manifestation of acute heart failure, with persistently high mortality rates and a lack of recent therapeutic breakthroughs. Accurate risk prediction is crucial in clinical decision-making and the design of future clinical trials. We aimed to validate the CLIP score, a biomarker-based risk score comprising cystatin C, lactate, interleukin-6 and NT-proBNP, for predicting mortality in acute coronary syndrome (ACS) related CS, and to compare its predictive value with the previously published CardShock risk score. The study is a post hoc analysis of the CardShock Study, a prospective, observational European multicentre study on CS. The CLIP score was calculated 12h after hospital admission, and its ability to predict 90-day mortality was assessed using are under the curve (AUC) of the receiver-operating characteristics (ROC) curve analysis. The discriminative ability of the CLIP score was compared with the CardShock risk score by comparing the AUC's. The cohort was dichotomized into low and high risk groups by the optimal cut-off value derived from the ROC analysis of the CLIP score. Kaplan-Meier curves were constructed to evaluate risk stratification when combining the CLIP and CardShock risk scores. The cohort (n=121) comprised 77% (n=93) men and the median age was 67years (IQR 61-76). A total of 21% (n=25) of the patients had non-ACS related CS. The CLIP score demonstrated appropriate predictive accuracy for 90-day mortality (AUC 0.84, 95% CI 0.77-0.91), comparable with the CardShock risk score (AUC 0.77 [95% CI 0.69-0.85]; P=0.064 for comparison). A CLIP score cut-off of 0.28 stratified patients into high risk (65% mortality) and low risk (16% mortality) groups. In addition, incorporating the CLIP score enhanced risk stratification in all CardShock risk score categories. The CLIP score, calculated within 12h of hospital admission, accurately predicted 90-day mortality in CS and complemented the CardShock risk score. The biomarker-based score has potential utility in dynamic mortality risk assessment and could inform clinical management and trial design.

Association between adjuvant component of perioperative chemotherapy and survival outcomes in resected gastric cancer (GC).

378 Background: Perioperative chemotherapy is the standard of care for resectable GC but many patients do not proceed to or complete adjuvant chemotherapy (AC). It remains unclear whether AC following neoadjuvant chemotherapy (NAC) improves survival. Methods: Patients with GC who received NAC and underwent curative-intent gastrectomy from 2006-2022 were identified from an institutional database. Patients with mismatch repair-deficient/microsatellite instability-high tumors, GEJ tumors, M1 disease, neoadjuvant radiotherapy, total neoadjuvant intent treatment, incomplete NAC (<66% of planned cycles), and incomplete data were excluded. A lymph node ratio (LNR) risk cutoff was determined using maximally selected rank statistics. Kaplan-Meier analysis with log-rank tests were used to compare overall survival (OS) and disease-free survival (DFS). Cox proportional hazards regression models were used to identify independent predictors of OS and DFS. All analyses were performed in R statistical software. Results: Of 340 patients included, 264 (78%) received AC. Most common reasons for incomplete AC were postoperative complications (20%), poor performance status (16%), minimal pathologic response to NAC (14%), patient choice (14%), and NAC toxicity (9%). Median follow-up was 6.4 years. In the overall cohort, there was no significant difference in OS (median 10 vs. 8.3 years; p=0.14) or DFS (7.0 vs. 7.5 years; p=0.12) between AC and non-AC groups. In node-negative (ypN-) patients (n=170), there was no association between receipt of AC and OS (12 vs. 10 years; p=0.6) or DFS (12 vs. 10 years; p=0.8). On univariable analysis, lack of AC receipt was not associated with shorter OS (p=0.3) or DFS (p=0.4). In the node-positive (ypN+) cohort (n=170), AC receipt was associated with significantly longer DFS (4.8 vs. 2.7 years; p=0.031) but not OS (5.5 vs. 2.8 years; p=0.071). However, on multivariate analysis, AC only showed a non-significant trend towards longer DFS (HR 0.77 [95% CI 0.49-1.19]; p=0.20). High-risk patients based on LNR (LNR>0.0684; n=112) who received AC (n=87; 78%) had longer OS (p=0.033) and DFS (p=0.014). No such differences were observed in the low risk LNR subgroup (LNR<0.0684; n=227). Conclusions: Following NAC, AC was not associated with improved survival in patients with ypN- GC. The association between AC and survival in ypN+ GC remains unclear but LNR may be used to identify patients with ypN+ disease who may benefit from AC. These observations require prospective validation but may have implications for clinical care and future trial design.

Impact of the Mediterranean Diet on Patients With Psoriasis: Protocol for a Randomized Controlled Trial.

Psoriasis is an inflammatory disease primarily treated through molecular-targeted therapies. However, emerging evidence suggests that dietary interventions may also play a role in managing inflammation associated with this condition. The Mediterranean diet (MedDiet), prevalent in southern European countries, has been widely recognized for its ability to reduce cardiovascular mortality, largely due to its anti-inflammatory properties. This anti-inflammatory potential has prompted interest in exploring the MedDiet's role in immune-mediated diseases, including psoriasis. Observational studies have indicated potential benefits, such as reductions in the Psoriasis Area and Severity Index. However, there is a need for well-designed clinical trials to address the methodological limitations of these studies and to establish specific dietary recommendations for psoriasis. This study aims to evaluate the impact of an intensive dietary intervention based on the MedDiet in patients with psoriasis. The study will assess the effects of this intervention on skin involvement, metabolic parameters, and inflammatory cytokines. In addition, the emotional well-being and quality of life of participants will be evaluated using validated questionnaires. A methodological analysis will also be conducted to enhance the design of future large-scale clinical trials. An open-label, single-blinded (evaluator) randomized controlled trial was designed to assess the impact of a high-intensity MedDiet intervention in patients with mild-to-moderate psoriasis. A total of 38 patients will be randomly assigned into 2 groups-an intervention group receiving the MedDiet intervention and a control group receiving standard care. The intervention group will participate in dietary education sessions aimed at adopting the MedDiet over 4 months, with monthly monitoring by experienced nutritionists. Participants will receive 500 mL of extra virgin olive oil per week, along with informative materials, recipes, and weekly menus. In contrast, the control group will receive standard low-fat diet recommendations without nutritionist monitoring. All participants will undergo a baseline visit, a 2-month follow-up visit, and a final visit at 4 months. Blood tests will be conducted at the beginning and end of the study. This study protocol was approved by the Institutional Review Board of the Hospital Ramón y Cajal (Madrid) in July 2023. Enrollment concluded in October 2024, with data collection set to finish by February 2025. The findings will be presented at national and international conferences and published in peer-reviewed journals. This protocol outlines the design of a clinical trial that implements the MedDiet in patients with psoriasis to evaluate its benefits on skin involvement, systemic inflammation, and quality of life. ClinicalTrials.gov NCT06257641; https://clinicaltrials.gov/study/NCT06257641. DERR1-10.2196/64277.

The PROPHECI trial: a phase II, double-blind, placebo-controlled, randomized clinical trial for the treatment of pseudoxanthoma elasticum with oral pyrophosphate

Background/aims.Pseudoxanthoma Elasticum (PXE, OMIM 264800) is an autosomal, recessive, metabolic disorder characterized by progressive ectopic calcification in the skin, the vasculature and Bruch’s membrane. Variants in the ABCC6 gene are associated with low plasma pyrophosphate (PPi) concentration. There is currently no reference treatment for this chronic debilitating disease.MethodsPROPHECI (PyROphosPHate supplementation to fight ECtopIc calcification in PseudoXanthoma Elasticum) is the first phase II, randomized, double-blind, placebo-controlled clinical trial (NTC 04868578) to evaluate the efficacy and safety of a daily oral PPi salt supplementation to attenuate and/or stabilize the progression of ectopic calcification in PXE patients. The primary endpoint is the change in arterial calcification volume quantified by non-contrast CT scan between baseline and 12 months of treatment. Secondary endpoints include the safety and efficacy of daily oral PPi administration on ocular and skin lesions and the evaluation of patients’ quality of life.DiscussionThe PROPHECI trial aims to provide safety and efficacy data on the use of daily oral PPi to reduce or stabilize ectopic calcification in PXE. It also aims to validate the best markers to include in the design of future trials for the treatment of PXE and other parent diseases.Trial registrationTrial registration number: NCT 04868578.References can be found on the ClinicalTrials.gov website: https://clinicaltrials.gov/study/NCT04868578?cond=Pseudoxanthoma%20Elasticum&intr=pyrophosphate&rank=2

Operational feasibility and reproducibility of serial echocardiographic parameters of left ventricular remodelling and function for evaluation of drug efficacy in multicentre clinical trial settings

Abstract Background Operational feasibility and reproducibility of echocardiographic (Echo) parameters are essential for planning interventional trials with surrogate imaging endpoints. Existing data from large cohort studies performed at institutions with high expertise in Echo may not be representative of the multicentre clinical trial settings where substantial variability in local standards and equipment exists. Purpose To assess feasibility of standardized Echo data acquisition, measurability, and reproducibility of key Echo endpoints in a large multicentre clinical trial. Methods ENDEAVOR was a phase 2b/3 multicentre, international, placebo-controlled trial investigating the effects of mitiperstat on symptoms and function in participants with heart failure (HF) and left ventricular ejection fraction (LVEF) >40%. Echo was used for efficacy assessment at 3 time points (baseline, 16 and 24 weeks). Echo data were acquired according to the study protocol at sites with various equipment and expertise and analysed centrally by an academic core laboratory. Key Echo metrics were LVEF, LV global longitudinal strain (GLS), LV mass, E/E’ and left atrial volume (LAV). LVGLS was measured from three apical views (4, 2, and 3-chamber) by 2DSTRAIN TomTec software. All images were evaluated for image quality using the scale from 1 (Very poor) to 5 (Excellent) and measured by a single reader. Results 711 participants at 142 sites in 18 countries were randomised in ENDEAVOR trial (mean age 72.4y, mean BMI 30.5kg/m2). A total of 2052 Echo exams were analysed: 735 at baseline, 661 at 16 and 656 at 24 weeks. Majority were of excellent to good (1282/62%) or adequate (732/36%) image quality. Doppler images and apical 4ch view were the most feasible to acquire, while apical 2ch view was the most challenging (Fig, A). LVEF, LV mass, E/E’ and LAV were measurable in most studies (88-96%), however fewer studies were interpretable for LVGLS (61% at baseline to 70% at week 24). When matching echo exams at 2 or 3 visits were analysed, the number of interpretable matches dropped more significantly for LVGLS (to 47% for 2 and 41% for 3 time points), while the proportion of interpretable matches for standard echo endpoints remained acceptable (>83% and >75%, respectively). A total of 82 scans were re-read for reproducibility. Most of the echo endpoints demonstrated good or excellent reproducibility, with LVGLS showing better reproducibility than LVEF (Fig, B). Conclusions We report feasibility of Echo data acquisition, measurability, and reproducibility of key parameters of LV remodelling and function in a large multicentre, international, placebo-controlled clinical trial in HF and EF>40%. These data will help to inform future trial design to drive drug development decision making.

Brain Age as a New Measure of Disease Stratification in Huntington's Disease.

Despite advancements in understanding Huntington's disease (HD) over the past two decades, absence of disease-modifying treatments remains a challenge. Accurately characterizing progression states is crucial for developing effective therapeutic interventions. Various factors contribute to this challenge, including the need for precise methods that can account for the complex nature of HD progression. This study aims to address this gap by leveraging the concept of the brain's biological age as a foundation for a data-driven clustering method to delineate various states of progression. Brain-predicted age, influenced by somatic expansion and its impact on brain volumes, offers a promising avenue for stratification by stratifying subgroups and determining the optimal timing for interventions. To achieve this, data from 953 participants across diverse cohorts, including PREDICT-HD, TRACK-HD, and IMAGE-HD, were meticulously analyzed. Brain-predicted age was computed using sophisticated algorithms, and participants were categorized into four groups based on CAG and age product score. Unsupervised k-means clustering with brain-predicted age difference (brain-PAD) was then employed to identify distinct progression states. The analysis revealed significant disparities in brain-predicted age between HD participants and controls, with these differences becoming more pronounced as the disease progressed. Brain-PAD demonstrated a correlation with disease severity, effectively identifying five distinct progression states characterized by significant longitudinal disparities. These findings highlight the potential of brain-PAD in capturing HD progression states, thereby enhancing prognostic methodologies and providing valuable insights for future clinical trial designs and interventions. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

DOP020 Baseline Microbiota and Differences in Donor-Recipient Richness as Determinants of Fecal Microbiota Transplantation Efficacy in Ulcerative Colitis

Abstract Background Rigorous donor preselection, strict anaerobic processing, and repeated faecal microbiota transplantation (FMT) administration did not improve outcomes for induction of clinical remission in the RESTORE-UC trial1. We studied the luminal, and mucosal microbiota composition as well as gene expression throughout the RESTORE-UC study, to further understand the results and instruct future FMT trial design. Methods The RESTORE-UC trial was a multi-centric double-blind, sham-controlled randomized trial. Patients with moderate to severe UC (total Mayo 4-10) were randomly allocated to receive 4 anaerobic-prepared allogenic or autologous donor FMT. Mucosal biopsies were collected for RNA- and 16S sequencing at week 0 and 8. Quantitative microbiota profiling was performed on donor samples, and in patients at weeks 0, 1, 2, 3, 4, 8, 12, 26, and 52 (n=756). Clinical success (steroid free clinical remission) and -response (≥3 points or ≥50% reduction in combined Mayo subscores for rectal bleeding and stool frequency) were evaluated at week 8. Metagenomic success (week 8) was defined as restoration of eubiosis (Bacteroides 2 (B2) to non-B2 enterotype) and failure was considered with subtypes being no transition, non-B2 to other non-B2 transition, lead dysbiosis (non-B2 to B2), and maintenance of dysbiosis (B2 to B2). Results Baseline beta diversity (metric for overall microbial similarity) was significantly associated with future clinical and metagenomic success (resp. p=0.035; p=0.003). Similar trends were observed at week 8 (resp. p=0.056; p=0.001). Restoration of eubiosis was characterized by a rapid increase in bacterial richness after the first FMT administration, which was maintained up to 12 months after intervention (Fig A). A greater difference (Fig B) in donor-recipient richness determined the metagenomic success (p=0.06) and clinical response (p=0.01), while this was not observed for clinical success (p=0.16). Metagenomic success was accompanied by increased engraftment after FMT (Fig C, p<0.01). Independently from clinical success, patients with dysbiotic faecal communities at baseline had distinctive mucosal communities in their intestinal biopsies (p<0.01), which were significantly changed in samples where eubiosis was restored (p=0.012), but not in those where clinical success was observed (p=0.34). However, this could be explained by the low overall response rate. No specific transcriptomic profiles in mucosal biopsies at baseline were reminiscent of metagenomic (p=0.24), nor clinical success (p=0.22). Conclusion Patient and donors should be rigorously selected in future FMT trials, and selection should be based on microbial composition and by obtaining a great difference in richness between receptor and donor. References 1 Caenepeel*, Deleu*, Vazquez* et al., 2024

P1120 ‘Early’ surgery for ileocaecal Crohn’s disease: a study of the patient perspective

Abstract Background Surgery for Crohn’s disease (CD) is considered when medical therapy is unsuccessful. However earlier bowel resection may offer more stable remission for localised luminal ileocaecal disease. The adoption of earlier surgery into practice comes with challenges, reflected by the difficulty in recruiting participants into trials of surgical treatment. We aimed to establish the acceptability of, and potential barriers to, early surgery from a patient perspective through a multicentre qualitative study. Methods Patients with ileocaecal CD from 8 centres across the United Kingdom (including both specialist IBD centres and non-specialist hospitals) were recruited, using purposive sampling, to participate in semi-structured interviews. Interviews were audio-recorded and transcribed. Recruitment continued until data saturation was achieved. Data were analysed thematically; 50% of the data were coded independently by two researchers. Results Twenty-nine participants were interviewed (14 males, 17 with a previous bowel resection, median time since diagnosis 6 years (8 months – 10 years), median age 34 years (22-71), 4 non-white patients). The themes and subthemes identified are summarised in Table 1. Participants with a previous bowel resection reported that surgery was not offered to them until they had tried several drugs or until disease complications had ensued; they described a poor quality of life prior to their operation. Surgery-naïve patients viewed a bowel resection as a last resort measure. There were many accounts of surgery being framed negatively by clinicians when offering treatment. Only one patient was aware of the benefits of early surgery. However, even participants with a good surgical outcome viewed surgery negatively; patients generally wanted to avoid an operation because of the risk of a stoma and the potential for complications. Conclusion This is the first study investigating the gap between the evidence-base and clinical practice around the management of luminal ileocaecal CD. Patients’ views of treatment are influenced by their clinicians’. In our previous study investigating the clinician perspective on early surgery, clinician-participants were proponents of early surgery. This is in contrast with the findings of this study where patients reported being offered a resection late in the pathway. Surgery should be discussed sooner with patients, ideally as part of a multidisciplinary team consultation. It is possible that patients will still prefer medical therapy to surgery. This has implications for the design of future trials comparing surgery to medical therapy for ileocaecal CD – recruitment into randomised trials may remain difficult in the face of strong patient (and/or clinician) preferences. References Ponsioen CY, de Groof EJ, Eshuis EJ, Gardenbroek TJ, Bossuyt PMM, Hart A, et al. Laparoscopic ileocaecal resection versus infliximab for terminal ileitis in Crohn’s disease: a randomised controlled, open-label, multicentre trial. Lancet Gastroenterol Hepatol. 2017;2(11):785-92. Husnoo N, Gana, T, Hague AG, Khan Z, Morgan JL, Wyld L, Brown SR. Is early bowel resection better than medical therapy for ileocolonic Crohn’s disease? A systematic review and meta-analysis. Colorectal Dis. 2023; 25(6): 1090-1101. Husnoo N, Morgan JL, Wyld L, Brown SR, P230: The challenges of implementing early surgery for terminal ileal Crohn’s disease – a qualitative study of the clinician perspective, British Journal of Surgery, Volume 111, Issue Supplement_2, March 2024, znae046.119,

Efficacy of lactoferrin supplementation in pediatric infections: A systematic review and meta-analysis.

Pediatric infections account for approximately one-third of all deaths in children under 5 globally. Lactoferrin (LF) supplementation has the potential to reduce infection-related morbidity due to its antimicrobial, anti-inflammatory and immunoregulatory properties. We conducted a systematic review and meta-analysis of oral LF supplementation randomized controlled trials (RCT) in population under 18 years old. The primary outcomes were infection-associated outcomes: late onset sepsis (LOS), diarrhea, and upper respiratory infections (URI). We also analyzed mortality among LOS studies. Of 1,594 citations identified, 25 studies met eligibility criteria, including 10 studies of LOS, 14 of diarrhea and 8 of URI. LF supplementation was associated with fewer patients with culture-proven or probable neonatal LOS compared to placebo (OR: 0.60; 95% CI: 0.42 to 0.86), with fewer patients with diarrhea compared to placebo in children (OR: 0.56; 95% CI: 0.41 to 0.75), and no significant fewer patients with URI (OR: 0.61; 95% CI: 0.27 to 1.40). Before LF can be used as a public health intervention, it is necessary to refine some aspects of the design of future trials. Ideally these trials should be conducted in countries with the highest burden of infections, where the potential benefit is expected to have the largest impact.

Benchmarking the Efficacy of Salvage Systemic Therapies for Recurrent Meningioma: A RANO Group Systematic Review and Meta-analysis to Guide Clinical Trial Design.

Despite advances in our understanding of the molecular underpinnings of meningioma progression and innovations in systemic and local treatments, recurrent meningiomas remain a substantial therapeutic challenge. The objective of this systematic review and meta-analysis is to provide a historical baseline, contemporary analysis, and propose a "rate of probable interest" to inform future clinical trial design and development on behalf of the RANO meningioma group. PubMed, ClinicalTrials.gov, and ASCOpubs databases were screened for clinical trials evaluating the activity of systemic therapies for adults with recurrent meningiomas. The pooled progression-free survival at 6-months and 1-year (PFS-6 and PFS-1 year) values were calculated using the random effects technique with I-squared indices. The pooled PFS-6 and PFS-1 year rates for recurrent WHO grade 1 meningiomas were 43.6% (95% CI: 22.7-67.0%, I2=80%) and 21.7% (95% CI: 6.2-53.9%, I2=76%), and for grade 2-3 meningiomas, the PFS-6 was 38.0% (95% CI: 28.3-48.8%, I2=68%). In targeted therapy group, PFS-6 and PFS-1 year rates stood at 62.0% (I2=58%) and 49.0% (I2=63%) for grade 1, while for grade 2-3 tumors, the PFS-6 rate with targeted therapy and immunotherapy was 42.1% (I²=60%) and 46.0% (I²=0%), respectively. The benchmarks were set at 67% and 54% for PFS-6 and PFS-1 year for grade 1 tumors, and PFS-6 of 49% for grade 2-3 tumors. Several studies have reported outcomes in patients with recurrent meningiomas testing a variety of agents with modest, but variable and progressively increasing activity. In this context, we recommend new benchmarks for future trials to define efficacy of future investigational therapies.

Feasibility and acceptability of a telephone-based ACT intervention for caregivers (TACTICs) of adults with Alzheimer’s disease and related dementias (ADRD): a randomized pilot during the COVID-19 pandemic

Objectives Examine the feasibility, acceptability, and preliminary effects of the Telephone Acceptance and Commitment Therapy Intervention for Caregivers (TACTICs) on dementia caregivers’ anxiety, depression, caregiver burden, suffering, and anticipatory grief. Method A 2-arm pilot randomized trial with dementia caregivers ≥ 21 years old with clinically elevated anxiety or anxiety-related functional interference. Two cohorts were recruited at the beginning and end of the first year of the COVID-19 pandemic. Intervention participants received 6 telephone sessions delivered by a non-licensed interventionist and control participants received readings and a list of dementia caregiver support groups in their area. Outcomes were measured at baseline, post-intervention, and at 3 and 6 months. Feasibility was measured by enrollment rates, completion rates, and adherence to TACTICs by interventionists. Acceptability was measured with participant satisfaction surveys. Results TACTICs was feasible and acceptable with 96% enrollment, 98.6% adherence, 65.5% completion, and a mean satisfaction score of 9.35 out of 10 (SD 0.91). The TACTICs group showed clinically relevant reductions in anxiety post-intervention (SRM 4.1, 95% CI [2.4,5.8]), however reductions were not significantly different from the control group (p = 0.98). Conclusion Implementation of TACTICs during the COVID-19 pandemic was feasible and acceptable. The preliminary outcomes were not as strong as expected. The results will inform the design of future trials with larger samples.

Comprehensive analysis of targetable mutations and tumor microenvironment in urachal cancer

Urachal cancer, a rare malignancy, generally presents in the clinical setting with advanced stages of disease. Systemic treatment with chemotherapy is generally utilized in this setting. However, there remains a paucity of data on the effectiveness of immune checkpoint inhibitors or targeted therapies for urachal cancer. We analyzed the genomic profile of urachal cancer in order to identify potentially targetable mutations and evaluate the tumor microenvironment. 42 urachal samples were retrospectively analyzed. Our results showed that TP53, GNAS and KRAS mutations were common in urachal cancer with increased prevalence of TP53 mutation in urachal cohorts without MAPK-alterations. The tumor microenvironment demonstrated increased NK cells in MAPK-altered urachal cancer. Finally, we show that urachal cancer shares genomic and transcriptomic similarity with colorectal cancer compared to bladder cancer. This study provides new insights into the molecular profiles of urachal tumor samples and possibility of association with colorectal cancer that might guide future clinical trial design.

Combination Antithrombotic Therapy for Reduction of Recurrent Ischemic Stroke in Intracranial Atherosclerotic Disease.

Stroke secondary to intracranial atherosclerotic disease (ICAD) is associated with high recurrence risk despite currently available secondary prevention strategies. In patients with systemic atherosclerosis, a significant reduction of stroke risk with no increase in intracranial or fatal hemorrhage was seen when rivaroxaban 2.5 mg twice daily was added to aspirin. However, there are no trials in ICAD using this combination. To facilitate the design of future ICAD trials, the CATIS-ICAD study (Combination Antithrombotic Treatment for Prevention of Recurrent Ischemic Stroke in Intracranial Atherosclerotic Disease) assessed (1) the feasibility of recruitment, (2) the safety of low-dose rivaroxaban plus aspirin compared with standard-of-care antiplatelet therapy, and (3) trends toward efficacy. This was a prospective, randomized, open-label, blinded end point pilot trial conducted in 10 Canadian centers. Eligible participants aged ≥40 years, with acute ischemic stroke or high-risk transient ischemic attack, were randomly assigned in a 1:1 ratio to receive low-dose rivaroxaban plus aspirin or aspirin alone within 7 to 100 days of their index event. The primary safety outcome was hemorrhagic stroke. The main efficacy end point was the composite of ischemic stroke or covert brain infarct on magnetic resonance imaging at the end of the study. A total of 101 participants were randomized. Average enrollment was 10 participants/site per year. Average follow-up was 20 months. Median time from index stroke to randomization was 67 days. The median age of participants was 67 years (±10.94), and 29% of participants were women. There was no hemorrhagic stroke in either arm. The composite efficacy outcome was less frequent in the combination arm (15.7%) compared with the aspirin arm (24.0%), with a hazard ratio of 0.78 ([95% CI, 0.32-1.93]; P=0.59) favoring the intervention. A multicenter randomized trial comparing the combination of low-dose rivaroxaban and aspirin in patients with recent ischemic stroke or transient ischemic attack due to ICAD is feasible and appears safe without an increased risk of hemorrhagic stroke. A numerical trend toward efficacy for the composite primary end point of symptomatic ischemic stroke and covert infarcts was observed. These findings will inform the design of a phase III trial. URL: https://www.clinicaltrials.gov; Unique identifier: NCT04142125.

Registries on transcatheter edge-to-edge repair in heart failure: Current evidence and future perspectives.

Secondary mitral regurgitation (SMR) and tricuspid regurgitation (TR) are the most common valvular heart diseases in patients with heart failure (HF). Transcatheter edge-to-edge repair (TEER) devices designed for treating MR and TR have been successfully tested in randomized controlled trials, but methodological issues have often challenged their interpretation. This manuscript aimed to provide an overview of TEER registries on SMR and TR in HF, highlighting their key features, describing clinical characteristics and outcomes of patients receiving these devices, and exploring the available data limitations. PubMed, Web of Science, and EMBASE were searched for registries reporting on TEER in SMR or TR. Registries were excluded if single-centre and with <100 patients. Twenty-six registries (46% prospective, 12% ongoing), including a total cohort of 18 925 patients, were retrieved for TEER in SMR, and six registries (50% retrospective, 33% ongoing) reported on the use of TEER for TR in a total cohort of 1412 patients. Limited geographical representativity outside North America and Europe, high number of missing values, and inconsistency in data reporting were the main existing evidence limitations. Registries on TEER represent a key data source in a setting where it is difficult to conduct randomized controlled trials. However, limitations in design, patient characterization, and outcomes reporting restrain their use. A novel conceptual framework for future prospective TEER registries, as proposed in this document, might inform current practice, address relevant clinical questions and future trial design.

Pharmacist-led DE-eSCALation of opioids post-surgical dischargE (DESCALE) - A multi-centre, non-randomised, feasibility study protocol.

Opioids are frequently prescribed for short-term acute pain following surgery. Used appropriately, opioids deliver extremely favourable pain relief. Used longer than 90-days, however, can result in health complications, including unintentional overdose and addiction. Globally, >40 million people are dependent on opioids and annually >100,000 die from opioid misuse. With >4.7 million surgical procedures occurring annually in the United Kingdom it is imperative that opioid-use is managed upon discharge. A declining General Practitioner (GP) workforce and increased patient numbers, however, means gaps in healthcare during transfer of care. Here we report a mixed-methods protocol to understand the feasibility, and acceptability of a clinical pharmacist (CP)-led early opioid deprescribing intervention for discharged surgical patients. DESCALE is a multicentre, non-randomised, pragmatic feasibility study. Participants aged ≥18 years who have undergone a surgical procedure at a single NHS trust in Southeast England and discharged with opioids and without a history of long-term opioid use, cancer diagnosis or study contraindications will be offered a Medicines Use Review (MUR) within 7-10 days of discharge. The MUR will be delivered by CPs at participating GP practices. Feasibility outcomes will focus on recruitment, fidelity of CPs to deliver the MUR, and barriers within primary care that affect delivery of the intervention, with a maximum sample size of 100. Clinical outcomes will focus on the number of participants that reduce or stop opioid use within 91 days. Prescribing, medical, surgical, and demographic data for individual participants will be collected and analysed to inform future trial design. Qualitative interviews with participants and associated healthcare professionals will explore acceptability and implementation of the intervention. Data collected with respect to opioid use post-surgery, feasibility and acceptability of the intervention, patient experience and outcome data will inform the design of future research and larger clinical trials.

Characteristic of Immunotherapy Trials in Head and Neck Squamous Cell Carcinoma: 2013-2023.

This research provides a comprehensive analysis of immunotherapy clinical trials for head and neck squamous cell carcinoma, aiming to enhance future trial designs. We analyzed all clinical trials focused on head and neck squamous cell carcinoma immunotherapy registered on ClinicalTrials.gov from January 1st, 2013, to December 31st, 2023, examining general characteristics, methodological features, and types of immunotherapeutic drugs. The analysis included 727 trials, with 687 interventional (94.50%) and 40 observational (5.50%). Most trials were small-sized (64.37%), single-centered (56.67%), non-blinded (94.76%), and non-randomized (72.93%). Over half of the trials were conducted in North America (55.71%), but trials in Asia increased significantly in the past 5 years (9.88% vs. 32.38%, p < 0.001). Only 20.63% of completed trials updated outcomes, with most results published 6-12 months after primary completion (55.13%). Immune checkpoint inhibitors were the predominant focus, and neoadjuvant immunotherapy was the main regimen in trials with resectable head and neck squamous cell carcinoma (74.83%). There has been a gradual increase in clinical trials over the past decade, with most being interventional. Delays or absences in outcome submission were prevalent. Novel immunotherapeutic drugs and treatment regimens are a significant focus.

Update on the roles of regular daily rhythms in combating brain tumors.

An endogenous time-keeping system found in all kingdoms of life, the endogenous circadian clock, is the source of the essential cyclic change mechanism known as the circadian rhythm. The primary circadian clock that synchronizes peripheral circadian clocks to the proper phase is housed in the anterior hypothalamus's suprachiasmatic nuclei (SCN), which functions as a central pacemaker. According to many epidemiological studies, many cancer types, especially brain tumors, have shown evidence of dysregulated clock gene expression, and the connection between clock and brain tumors is highly specific. In some studies, it is reported that the treatment administered in the morning has been linked to prolonged survival for brain cancer patients, and drug sensitivity and gene expression in gliomas follow daily rhythms. These results suggest a relationship between the circadian rhythm and the onset and spread of brain tumors, while further accumulation of research evidence will be needed to establish definitely these positive outcomes as well as to determine the mechanism underlying them. Chronotherapy provides a means of harnessing current medicines to prolong patients' lifespans and improve their quality of life, indicating the significance of circadian rhythm in enhancing the design of future patient care and clinical trials. Moreover, it is implicated that chronobiological therapy target may provide a significant challenge that warrants extensive effort to achieve. This review examines evidence of the relationship of circadian rhythm with glioma molecular pathogenesis and summarizes the mechanisms and drugs implicated in this disease.

Key considerations for combination therapy in Alzheimer's clinical trials: Perspectives from an expert advisory board convened by the Alzheimer's drug discovery foundation.

There is growing consensus in the Alzheimer's community that combination therapy will be needed to maximize therapeutic benefits through the course of the disease. However, combination therapy raises complex questions and decisions for study sponsors, from preclinical research through clinical trial design to regulatory, statistical, and operational considerations. In January 2024, the Alzheimer's Drug Discovery Foundation convened an expert advisory board to discuss the key considerations in each of these areas. Experts agreed on the need to prioritize a combination therapy approach that encompasses a wide range of targets associated with aging and the underlying biology of Alzheimer's disease. Progress in combination therapy could be accelerated by leveraging preclinical research and Phase 1 and 2A trials to identify the most promising combinations for further development, exploring repurposed agents with available preclinical and clinical data, building collaborations across sectors to support operational challenges, and planning for the likely impact of anti-amyloid beta-protein monoclonal antibody therapies on future clinical trial designs.

Estimating direct tissue effects versus weight loss effects of incretin-based drugs for obesity on various chronic conditions.

The extent to which newer, incretin-based drugs for obesity improve disease outcomes via weight loss versus the direct effects of these drugs is the subject of intense interest. Although reductions in major adverse cardiovascular events appear to be predominantly driven by the direct tissue effects of such drugs, the associated weight loss effects must be relevant to the benefits observed in other major outcomes, albeit to differing extents. In this Personal View, we draw on evidence to support that weight loss is at least partly responsible (albeit to differing extents) for the reported benefits of incretin-based drugs for obesity in people living with heart failure with preserved ejection fraction, hypertension, chronic kidney disease, and type 2 diabetes. Concurrently, we propose that drug-induced weight loss is largely responsible for the reported improvements in osteoarthritis, obstructive sleep apnoea, and metabolic dysfunction-associated steatohepatitis outcomes. However, more evidence is needed to solidify these observations, including, when possible, trials comparing the effects of incretin-based drugs for obesity with calorie-reduced diets on both outcomes and mechanistic pathways. Such evidence has implications for public health and the design of future trials of novel drugs for obesity.

Advancing Drug Development in Myelodysplastic Syndromes.

Myelodysplastic syndromes/neoplasms (MDS) are heterogeneous stem cell malignancies characterized by poor prognosis and no curative therapies outside of allogeneic hematopoietic stem cell transplantation. Despite some recent approvals by the United States Food and Drug Administration (FDA), (e.g., luspatercept, ivosidenib, decitabine/cedazuridine and imetelstat), there has been little progress in the development of truly transformative therapies for the treatment of patients with MDS. Challenges to advancing drug development in MDS are multifold but may be grouped into specific categories including criteria for risk stratification and eligibility, response definitions, time-to-event endpoints, transfusion endpoints, functional assessments, and biomarker development. Strategies to address these challenges and optimize future clinical trial design for patients with MDS are presented here.