Results Of Trial Research Articles

Bempedoic Acid for Prevention of Cardiovascular Events in People With Obesity: A CLEAR Outcomes Subset Analysis.

Obesity and hypercholesterolemia independently increase cardiovascular disease risk. This analysis evaluated the efficacy and safety of bempedoic acid in people with obesity participating in the CLEAR (Cholesterol Lowering via Bempedoic Acid [ECT1002], an ACL-Inhibiting Regimen) Outcomes trial. CLEAR Outcomes randomized 13 970 patients to daily bempedoic acid 180 mg or placebo. Exploratory outcomes including major adverse cardiovascular events-4 (cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization), low-density lipoprotein cholesterol, hs-CRP (high-sensitivity C-reactive protein), weight change, and safety were assessed over a median of 40.7 months in 6177 patients with baseline body mass index ≥30 kg/m2. In people with obesity, bempedoic acid resulted in placebo-corrected reductions in low-density lipoprotein cholesterol of -22.5% and hs-CRP of -23.2% at 6 months. Bempedoic acid treatment resulted in a major adverse cardiovascular events-4 reduction of 23% (hazard ratio [HR], 0.77 [95% CI, 0.67-0.89]) versus placebo. Nonfatal and fatal MI were reduced by 32% (HR, 0.68 [95% CI, 0.53-0.86]), coronary revascularization was reduced by 24% (HR, 0.76 [95% CI, 0.63-0.92]), and fatal and nonfatal stroke were reduced by 36% (HR, 0.64 [95% CI, 0.45-0.89]) compared with placebo. At month 36, mean±SD change in weight from baseline was -2.3 (6.3) kg for bempedoic acid and -1.4 (6.1) kg for placebo. Adverse events were reported in 87.4% of bempedoic acid patients and 86.7% of placebo patients. The mean±SD change in uric acid at 6 months was 0.81 (1.26) mg/dL for bempedoic acid versus -0.04 (1.05) mg/dL for placebo. Among people with obesity, bempedoic acid reduced major adverse cardiovascular events, low-density lipoprotein cholesterol, and hs-CRP, with a safety profile consistent with previous reports. URL: https://www.clinicaltrials.gov; Unique Identifier: NCT02993406.

Apolipoprotein C3 and risk of cardiovascular events and death in patients on optimized statin treatment after recent acute coronary syndrome.

Apolipoprotein (Apo) C3 has been associated with incident coronary heart disease and major adverse cardiovascular events (MACE). Whether ApoC3 levels predict risk in patients with acute coronary syndrome (ACS) on optimized statin treatment is unknown. ApoC3 was measured by mass spectrometry at baseline (n=11,956) and after 4 months' treatment (M4; n=11 176) with alirocumab or placebo in the ODYSSEY OUTCOMES trial. Patients with fasting triglycerides >400 mg/dL were excluded. The association of baseline ApoC3 with risk of MACE or death was assessed in post hoc adjusted Cox regression models and spline analyses adjusted for treatment and ApoB. In adjusted models in the alirocumab group we determined association of ApoC3 change from baseline to M4 with subsequent risk of MACE and death. Median (Q1, Q3) baseline ApoC3 concentration was 85 (65, 113) mg/L. With adjustment for ApoB, baseline ApoC3 showed no clinically meaningful relationship to risk of MACE or death in spline analyses and no association with MACE (P=0.89) or death (P=0.70) in Cox regression analyses. Alirocumab reduced ApoC3 modestly by median -10 (-27, -5) mg/L (P<0.0001) and reduced MACE (10.1% vs 12.1%; P=0.0006) and death (3.5% vs 4.2%; P=0.045) versus placebo. However, the change in ApoC3 on alirocumab did not predict subsequent MACE or death. In patients with recent ACS on optimized statins without severe hypertriglyceridemia, neither baseline ApoC3 (accounting for ApoB) nor ApoC3 change with alirocumab predicted MACE or death. It is uncertain whether targeted therapies producing larger reductions in ApoC3 from higher baseline levels will affect cardiovascular risk.

Study protocol of a pilot randomised controlled trial assessing the feasibility and acceptability of RecoverEsupport: a digital health intervention to enhance recovery in women undergoing surgery for breast cancer

IntroductionInternationally, breast cancer is the second most diagnosed cancer with approximately 2.3 million people diagnosed each year. 40% will require a mastectomy which has an average length of hospital stay...

Methods to address functional unblinding of raters in CNS trials

Treatment-emergent adverse events (TEAEs) associated with the unique properties of a pharmaceutical product may functionally unblind clinician ratings, obscure true medication effects, and affect confidence about clinical trial results. Central nervous system studies are particularly susceptible to functional unblinding because they rely on relatively subjective symptom assessments. Two different methods were used to examine possible functional unblinding in pooled data from three recent five-week, double-blind, placebo-controlled trials of xanomeline and trospium chloride (formerly known as KarXT) in participants with schizophrenia experiencing acute psychosis. Xanomeline/trospium is an M1/M4 muscarinic receptor agonist that may produce cholinergic side effects. First, we compared the scores of remote (site-independent) raters, blinded to TEAEs, who listened to audio recorded, site-based Positive and Negative Syndrome Scale (PANSS) interviews. Second, we conducted a post hoc analysis of participant subgroups with or without reported cholinergic-related TEAEs to ascertain whether cholinergic TEAEs influenced trial outcome. Remote ratings closely replicated 575 available “paired” site-based PANSS total scores at baseline and endpoint (intraclass correlation coefficient = 0.88 and 0.93, respectively). Both site-based and remote PANSS scores yielded significant improvement favouring xanomeline/trospium over placebo (both p < 0.0001) and yielded significantly greater treatment response (≥30% improvement from baseline) than placebo (both p < 0.0001). The significant improvement of PANSS scores favouring xanomeline/trospium over placebo was comparable in magnitude for all subgroups regardless of whether participants reported cholinergic-related TEAEs, or any TEAEs at all (all p < 0.001). In sum, the two different methods used to assess functional unblinding in these studies found no impact of cholinergic TEAEs, or any TEAEs, on the trial results. These methods may have utility across all clinical trials.

Symptom monitoring with electronic patient-reported outcomes during cancer treatment: final results of the PRO-TECT cluster-randomized trial.

Symptoms are often underdetected during cancer treatment. To determine if symptom monitoring with electronic patient-reported outcomes (PROs) improves clinical outcomes, we conducted a cluster-randomized trial in which 52 oncology practices were assigned to PRO or usual care. At PRO practices, patients with metastatic cancer were invited to complete weekly symptom surveys. Severe or worsening symptoms generated alerts to the care team. The primary outcome was overall survival, and secondary outcomes included emergency visits, time to deterioration of physical function, symptoms, health-related quality of life (HRQL) and patient satisfaction with PRO. Among 1,191 enrolled patients, there was no difference in survival (hazard ratio (HR) 0.99 (95% confidence interval (CI), 0.83-1.17); P = 0.86). Time to first emergency visit was significantly prolonged with PRO compared to usual care (HR 0.84 ((95% CI, 0.71-0.98); P = 0.03), with a 6.1% reduction in the cumulative incidence of emergency visits and fewer mean visits at 12 months with PRO (1.02 versus 1.30; P < 0.001). Benefits also significantly favored PRO for delayed deterioration of physical function (median 12.6 versus 8.5 months, HR 0.73; P = 0.002), symptoms (12.7 versus 9.9, HR 0.69; P < 0.001) and HRQL (15.6 versus 12.2, HR 0.72; P = 0.001), which remained significant when considering deaths in analyses. Most patients felt that PRO improved discussions with the care team (77.0% (188/244)), made them feel more in control of their care (84.0% (205/244)) and would recommend it to other patients (91.4% (223/244)). Patients completed 91.5% (20,565/22,486) of expected weekly symptom surveys. These findings demonstrate that symptom monitoring with PRO meaningfully improves clinical outcomes, the patient experience and utilization of services and should be included as a standard part of quality cancer clinical care. Future studies of PRO in clinical care should focus on these outcomes rather than mortality as primary endpoints. ClinicalTrials.gov registration: NCT03249090.

DAILY – A personalized circadian Zeitgeber therapy as an adjunctive treatment for alcohol use disorder patients: results of a pilot trial

DAILY – A personalized circadian Zeitgeber therapy as an adjunctive treatment for alcohol use disorder patients: results of a pilot trial

Shortening duration of untreated illness in young people with first episode eating disorders: protocol of a randomised controlled feasibility trial of a smartphone friendly multi-modal decision-making tool (FREED-M) to improve help-seeking

BackgroundEarly intervention gives young people the best chance to recover from eating disorders (EDs). An important focus of early intervention is shortening the time between a person first developing symptoms and starting treatment (duration of untreated eating disorder; DUED). Patient-related factors (e.g. poor mental health literacy and help-seeking difficulties) are strongly associated with DUED. The aims of our study are to co-design and test the feasibility of FREED-Mobile (FREED-M), an online intervention tool for young people with early-stage EDs. This tool aims to improve knowledge about EDs, increase motivation to seek treatment and teach early steps towards change or recovery, thus reducing DUED.MethodsWe will carry out a randomised controlled feasibility trial comparing the FREED-M tool with a control intervention where individuals are sign-posted to an ED charity website. The objectives of the proposed trial are to establish/estimate: (a) attrition rates at follow-up (primary feasibility outcome); (b) participant recruitment; (c) intervention uptake, completion rates and acceptability; (d) intervention effect sizes and standard deviations for outcomes to inform the sample size calculation for a large-scale randomised controlled trial (RCT); (e) stakeholder views on the intervention.We aim to recruit 116 participants (young people, aged 16–25, with first episode ED) from primary care, schools and universities, ED services and social media. Online assessments will be carried out at baseline, end of intervention and follow-up (weeks 0, 4 and 12 post-randomisation, respectively). Outcomes will include motivation and readiness to change, attitudes and intentions towards help-seeking, ED symptoms, mood and social functioning, and health-related quality of life. Additionally, we will carry out a qualitative evaluation of participants’ views of the intervention and study design.DiscussionThe results of this feasibility trial will inform adaptations to the intervention as needed, as well as the study design (e.g. sample size, primary outcomes) of a future large-scale RCT to assess the effectiveness of the FREED-M intervention. If effective, this novel, online intervention has the potential for wide dissemination and for substantially reducing DUED to improve long-term patient outcomes.Trial registrationISRCTN, ISRCTN15662055. Registered 27 July 2022, https://www.isrctn.com/ISRCTN15662055.

Interventions for the management of post-COVID-19 condition (long COVID): protocol for a living systematic review and network meta-analysis

BackgroundUp to 15% of survivors of COVID-19 infection experience long-term health effects, including fatigue, myalgia and impaired cognitive function, termed post-COVID-19 condition or long COVID. Several trials that study the...

Modelling Cardiorenal Protection with SGLT2 Inhibition in Type 1 Diabetes - An Analysis of DEPICT-1 and DEPICT-2.

Sodium-glucose co-transporter-2 (SGLT2) inhibitors improve glycemia and reduce insulin requirements in type 1 (T1D) and type 2 (T2D) diabetes. While SGLT2 inhibitors lower cardiovascular disease (CVD) and end-stage kidney disease (ESKD) risk in T2D, no dedicated cardiorenal outcome trials in T1D have been done to date. Using validated risk prediction models, this study evaluated the effect of SGLT2 inhibition on estimated CVD and ESKD risk in a T1D cohort. Demographics, medical history, and biomarkers were extracted from 1,473 participants with T1D enrolled in the Dapagliflozin Evaluation in Patients with Inadequately Controlled Type 1 Diabetes (DEPICT)-1 and -2 trials. Data at baseline, 24-, 52- and 56-weeks (four weeks post-drug cessation) were used to estimate 10-year CVD and five-year ESKD risk using the Steno T1 Risk Engine (SRE) and Scottish Diabetes Research Network (SDRN) risk prediction models. Risk reduction was determined based on relative change in risk from baseline between participants receiving dapagliflozin (pooled 5 and 10 mg) vs. placebo. Subgroup analyses were conducted by age, sex, diabetes duration, CVD risk and chronic kidney disease (CKD) status at baseline. The relative change in 10-year estimated CVD risk (SRE: -6.50% [-8.04, -4.95%] & SDRN: -6.77% [-8.40, -5.13%]; all P<0.001) and five-year ESKD risk (SRE: -4.48% [-7.68, -1.28%]; P=0.006) were lower at the end of 24 weeks of dapagliflozin treatment compared to placebo. Further, the greatest relative change in 5-year ESKD risk was observed at week 56 (SRE: -12.84% [-16.65, -9.03%]; P<0.001), in conjunction with an expected rise in estimated glomerular filtration rate post-drug washout. Subgroup analysis revealed larger relative lowering in 10-year CVD risk in those with CKD compared to those without (SRE: -11.3% vs -5.9%, & SDRN: -11.9% vs -6.1%, respectively; all Pinteraction<0.02). Dapagliflozin improves estimated CVD and ESKD risk in T1D participants, emphasizing the need for cardiorenal outcome trials in people living with T1D.

Drug Repositioning and Repurposing for Disease-Modifying Effects in Parkinson's Disease.

Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder and is characterized by progressive dopaminergic and non-dopaminergic neuronal loss and the presence of Lewy bodies, which are primarily composed of aggregated α-synuclein. Despite advancements in symptomatic therapies, such as dopamine replacement and deep brain stimulation, no disease-modifying therapies (DMTs) have been identified to slow or arrest neurodegeneration in PD. Challenges in DMT development include disease heterogeneity, the absence of reliable biomarkers, and the multifaceted pathophysiology of PD, encompassing neuroinflammation, mitochondrial dysfunction, lysosomal impairment, and oxidative stress. Drug repositioning and repurposing strategies using existing drugs for new therapeutic applications offer a promising approach to accelerate the development of DMTs for PD. These strategies minimize time, cost, and risk by using compounds with established safety profiles. Prominent candidates include glucagon-like peptide-1 receptor agonists, dipeptidyl peptidase-4 inhibitors, ambroxol, calcium channel blockers, statins, iron-chelating agents, c-Abl inhibitors, and memantine. Although preclinical and early clinical studies have demonstrated encouraging results, numerous phase III trials have yielded unfavorable outcomes, elucidating the complexity of PD pathophysiology and the need for innovative trial designs. This review evaluates the potential of prioritized repurposed drugs for PD, focusing on their mechanisms, preclinical evidence, and clinical trial outcomes, and highlights the ongoing challenges and opportunities in this field.

Clinically meaningful improvements after gene therapy for aromatic L-amino acid decarboxylase deficiency (AADCd) in the Peabody Developmental Motor Scale, Second Edition (PDMS-2) and correlation with Bayley-III scores and motor milestones

BackgroundAromatic L-amino acid decarboxylase deficiency (AADCd) is a rare genetic disorder characterized by movement disorders, motor and autonomic dysfunction, and developmental delays. The gene therapy eladocagene exuparvovec has become available in some regions; pooled clinical trial results demonstrate continuous long-term improvement in motor development and cognitive function. We sought to characterize clinically meaningful change in motor function, as measured by Total Peabody Developmental Motor Scales-Second Edition (PDMS-2) score, and assess correlations with cognition and language domains of the Bayley-III and motor milestone (MM) achievement.MethodsData from N = 30 patients from three single-arm clinical studies of eladocagene exuparvovec were analyzed. Anchor-based estimation of the meaningful score difference (MSD) of Total PDMS-2 score was conducted using mean-difference and receiver operating characteristic curve (ROC) approaches. MM achievement served as the anchor defining meaningful change.ResultsAn MSD of 40 points for Total PDMS-2 score was selected for analysis as it yielded specificity > 0.95 using the ROC approach, and generally aligned with the mean-difference approach. Cumulative incidence analysis reflected that 50% of patients treated with eladocagene exuparvovec may achieve the MSD of 40-point change in Total PDMS-2 score at 6 months, and 86% at 18 months. Correlations between measures were of large magnitude and improved over time (Month 6: r = 0.599 [p = 0.0032]; Month 18: r = 0.796 [p = 0.0002]; Month 60: r = 0.861 [p = 0.0007]).ConclusionsThe MSD of 40 points for Total PDMS-2 score enables the interpretation of changes observed in patients with AADCd, and suggests that treatment with eladocagene exuparvovec leads to significant improvements in motor and cognitive function.

Agronomic Performance of Faba Bean in Mediterranean Environments

The faba bean (Vicia faba) is an important grain legume that, despite decades of decline, is regaining interest in the Mediterranean basin due to an increasing demand for plant-based proteins and other ingredients, particularly for the food industry. However, the crop’s sensitivity to weather conditions (mainly drought and heat) as well as its high susceptibility to diseases hinder its yield performance and stability. For this reason, in this study, we present the results of multi-environment field trials conducted in southern Spain, where the performance of six new elite faba bean cultivars, developed through local breeding programs focused on selection for increased yield and chocolate spot (Botrytis fabae) resistance, was compared with two popular commercial cultivars. Data analysis across six diverse environments showed the significant effects of environment, genotype, and genotype-by-environment interaction (GEI) on yield and several morphologic traits. Grain yield was positively influenced by rainfall and negatively affected by high temperatures, with no evidence of damage due to cold temperatures. Stress tolerance indexes helped identify cultivars Omeya, Faraon Negro, and Navio6, which excelled across all metrics. The trials were intentionally conducted in broomrape (Orobanche crenata)-free plots, where chocolate spot emerged as the major biotic constraint, with the infection level highly influenced by rainfall. Significant differences were observed among accessions in their response to chocolate spot, with the cultivar Arrechana showing resistance. Overall, cultivars Omeya, Arrechana, Faraon Negro, Navio6, and Quijote demonstrated outstanding grain yield and excellent adaptation to the region.

Risk of Incident Diabetes Related to Lipoprotein(a), LDL Cholesterol, and Their Changes With Alirocumab: Post Hoc Analyses of the ODYSSEY OUTCOMES Randomized Trial.

Previous genetic and clinical analyses have associated lower lipoprotein(a) and LDL cholesterol (LDL-C) with greater risk of new-onset type 2 diabetes (NOD). However, PCSK9 inhibitors such as alirocumab lower both lipoprotein(a) and LDL-C without effect on NOD. In a post hoc analysis of the ODYSSEY OUTCOMES trial (NCT01663402), we examined the joint prediction of NOD by baseline lipoprotein(a), LDL-C, and insulin (or HOMA-insulin resistance [HOMA-IR]) and their changes with alirocumab treatment. Analyses included 8,107 patients with recent acute coronary syndrome on optimized statin therapy, without diabetes at baseline, assigned to alirocumab or placebo with median follow-up 2.4 years. Splines were estimated from logistic regression models. Lower baseline lipoprotein(a) and higher baseline insulin or HOMA-IR independently predicted 782 cases of NOD; baseline LDL-C did not predict NOD. Alirocumab reduced lipoprotein(a) and LDL-C without affecting insulin or NOD risk (odds ratio [OR] vs. placebo 0.998; 95% CI 0.860-1.158). However, in logistic regression, decreased lipoprotein(a) and LDL-C on alirocumab were independent, opposite predictors of NOD. OR for NOD for 25% and 50% lipoprotein(a) reductions on alirocumab were 1.12 (95% CI 1.01-1.23) and 1.24 (1.02-1.52). OR for NOD for 25% and 50% LDL-C reductions on alirocumab were 0.88 (95% CI 0.80-0.97) and 0.77 (0.64-0.94). Baseline lipoprotein(a) was inversely associated with risk of NOD. Alirocumab-induced reductions of lipoprotein(a) and LDL-C were associated with increased and decreased risk of NOD, respectively, without net effect on NOD. Ongoing trials will determine the impact of larger and longer lipoprotein(a) reductions on NOD.

Capturing the Additional Cardiovascular Benefits of SGLT2 Inhibitors and GLP-1 Receptor Agonists Beyond the Control of Traditional Risk Factors in People with Diabetes.

This study aimed to quantify the additional cardioprotective effects of sodium-glucose cotransporter 2 inhibitors (SGLT2is) and glucagon-like peptide-1 receptor agonists (GLP-1RAs) beyond the traditional risk factors control in individuals with type 2 diabetes (T2D). This helps calibrate the BRAVO diabetes simulation model to capture the total cardiovascular benefits of new diabetes medications accurately. We extracted patient characteristics and treatment efficacy data from four cardiovascular outcomes trials (CVOTs) of SGLT2is and four CVOTs of GLP-1RAs completed before May 2023. Using the BRAVO diabetes simulation model, we translated reductions in traditional risk factors (i.e., glycated hemoglobin; systolic blood pressure; low-density lipids; body mass index) from the newer drugs into risk reductions in cardiovascular outcomes (i.e., myocardial infarction (MI), stroke, congestive heart failure (CHF), and mortality) assuming the drug-associated risk reductions are only driven by traditional risk factors. Then we compared the simulated risk-factor-driven risk reductions of cardiovascular outcomes with observed risk reductions from the trials and calculated drug-specific incremental benefits (DIB). After accounting for the cardiovascular effects from traditional risk factors control, SGLT2is was associated with an additional 19% risk reduction in CHF (DIB: 0.81, 95% CI: 0.72-0.90). Furthermore, the uncalibrated model predicted a risk reduction in stroke with SGLT2is, which was not observed in CVOTs. This discrepancy highlights the need for an SGLT2i-specific calibrator to align the simulation results with the observed outcomes. In contrast, no additional cardiovascular benefit was associated with GLP-1RAs after controlling for traditional risk factors. Our study revealed that SGLT2is could further reduce CHF risks beyond the control of traditional risk factors but may offer additional pathways to offset overall benefits from traditional risk factor control in stroke risks. No additional cardiovascular benefits were observed for GLP-1RAs beyond traditional risk factor control. The BRAVO model calibration enhances cardiovascular outcome prediction with these newer antidiabetic therapies.

New bispecific antibodies in diffuse large B-cell lymphoma.

The CD20xCD3 T-cell-engaging bispecific antibodies are a highly active new treatment option for patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL). Epcoritamab and glofitamab have both been approved in over thirty countries as monotherapy for DLBCL after two prior treatment lines; odronextamab has recent European approval, and mosunetuzumab is active and is being developed as a combination partner. These agents can be safely combined with other immunotherapies and chemotherapy, and single-arm and randomised trial outcomes promise an expanding role for this class of drugs in earlier treatment lines. This review examines the clinical development of the CD20xCD3 bispecific antibodies in DLBCL, how the phase I and II trials inform their current use, and the key distinctions between the agents. We focus on the efficacy and safety of those bispecific antibodies most advanced in development. We also consider emerging understandings of resistance mechanisms. Finally, we review key ongoing trials and combinations and consider the potential future of bispecific antibodies within the sequence of available treatments for DLBCL.

Process evaluation of Project Daire: a food environment intervention that impacted food knowledge, wellbeing and dietary habits of primary school children

BackgroundProject DAIRE was a randomised-controlled, factorial design trial which aimed to improve children’s health-related quality of life, wellbeing, food knowledge and dietary habits via two multi-component interventions: Nourish and Engage. Nourish was an intervention aiming to alter the school food environment, provide food-based experiences and expose pupils to locally produced foods. Engage was an age-appropriate cross-curricular food education intervention incorporating food, agriculture, nutrition science and related careers. The purpose of this study was to conduct a process evaluation to evaluate DAIRE implementation, mechanisms of impact (MOI) and context to elucidate trial results, and inform scalable implementation of the DAIRE approach for successful future rollout.MethodsThe Medical Research Council’s (MRC) framework for process evaluation was followed. Formal (questionnaires designed for process evaluation) and informal (researcher records and communications) methods were used to collect quantitative and qualitative data during the DAIRE trial in relation to process evaluation. Quantitative data were analysed using descriptive statistics and qualitative data via thematic analysis to identify key themes.ResultsFifteen schools and 983 pupils (n = 495 6–7 year olds/Year 3 and n = 488 10–11 year olds/Year 7) were recruited for the 6-month DAIRE intervention; a 100% retention rate was observed at the school level and the interventions had a high level of pupil and teacher acceptability. Nourish schools delivered a higher mean dose of intervention elements (61.4%) than Engage (50%) schools but, overall, mixed implementation of both interventions occurred. DAIRE produced change through four key MOI: social learning, experimental learning, interactive engaging content and real-life connections. Lack of time was the main contextual barrier to implementation and lack of financial cost to schools indicated as a potential facilitator.ConclusionsThis process evaluation helped to identify important findings related to implementation, MOI and context. The most effective elements of the interventions which should be maintained include provision of interactive and engaging intervention elements at no financial cost to the school. Findings also identified suggestions for improvement including provision of increased teacher training, support and planning time, content reduction to facilitate easy integration, and implementation across the full academic year. A sustainable funding and resourcing mechanism is required for successful future roll-out across the UK and beyond.Trial registrationsThe original trial referenced in this process evaluation is registered as follows: National Institute of Health (NIH) U.S. National Library of Medicine Clinical Trials.gov (ID: NCT04277312; retrospectively registered 11th February 2020).

Efficacy of Asymmetric Myopic Peripheral Defocus Lenses in Spanish Children: 24-Month Randomized Clinical Trial Results

Background/Objectives: Asymmetric myopic peripheral defocus lenses (MPDLs) have proven to be effective in slowing the progression of myopia in Spanish children over a period of 12 months. The purpose of this study was to assess the MPDL spectacles’ efficacy in slowing myopia progression over a 24-month period in children. Methods: This study extends the follow-up period of the double-masked, prospective, and randomized clinical trial previously published to 24 months. Children from 6 to 12 years were assigned to two groups: a control group wearing spherotorical single vision lenses (SVLs) or a treatment group wearing MPDL lenses. Inclusion criteria included children with myopia less than −0.50 D, astigmatism below 1.50 D, and best-corrected visual acuity of at least 20/20. Participants underwent cycloplegic autorefractive examination and axial length (AL) measurements at the baseline and six and twelve months in the study already published, and twenty-four months later in the present study. Lifestyle factors, including outdoor activities and digital device use, were also assessed. Baseline characteristics, including age, refractive error, and AL, were comparable between groups. Dropout rates were 15.9%, with 14 participants lost to follow-up, distributed equally between the two groups. Results: After 24 months of follow-up, 69 children remained in this study, comprising 34 participants in the SVL cohort and 35 in the MPDL cohort. Over 24 months, the MPDL group showed significantly less AL elongation than the SVL group (0.27 ± 0.23 mm and 0.37 ± 0.24 mm; p = 0.0341). The mean relative AL increase was 1.10 ± 0.95% in the MPDL group, compared to 1.56 ± 1.02% in the SVL group (p = 0.0322). Younger children exhibited faster AL growth, while digital device use and outdoor activities did not affect AL changes. Conclusions: MPDL spectacle lenses substantially slowed myopia progression over a 24-month period, with 28.7% less progression in absolute AL growth and 29.8% in relative AL growth compared to SVL. These results indicate that MPDL lenses are an effective method for slowing myopia progression.

Immunotherapies to Nano-Immunotherapies: Advances in Immune Targeting in Bladder Cancer

Bladder cancer is among most common malignancies worldwide, with significant morbidity and mortality. Conventional treatment strategies for bladder cancer include transurethral resection, radical cystectomy and chemotherapy. However, the complex immune landscape of bladder cancer involves innate and adaptive immune components that either promote or suppress tumor progression. Upregulation of checkpoint molecules like PD-L1 and recruitment of immunosuppressive cells, contribute to immune evasion and treatment resistance. Immune checkpoint inhibitors such as nivolumab, pembrolizumab, avelumab, and atezolizumab have shown promising results in clinical trials and have been approved for metastatic and high-risk bladder cancer. Additionally, Bacillus Calmette-Guérin (BCG) immunotherapy has long been in use as bladder cancer treatment. Furthermore, natural killer cell-based therapies and novel immune targets like TIGIT and CD155 are under investigation to enhance anti-tumor immunity. However, challenges such as toxic side-effects, variable response rates and the need for predictive biomarkers persists. Nanotechnology offers promising solutions to improve immunotherapy outcomes. Recent advances include the use of gold nanoparticles, TLR agonist-loaded nanoparticles, and exosome-based delivery systems to boost immune responses. Additionally, nanovaccine strategies incorporating tumor-associated antigens and immune adjuvants show potential for personalized cancer immunotherapy. Here, we discuss the immune landscape of bladder cancer, explore the emerging immunotherapies being used as bladder cancer treatment, and discuss the advantages of using nanoparticles as carriers of immunotherapies against bladder cancer. By optimizing combination strategies, identifying novel immunotherapeutic targets, and leveraging nanotechnology for precision medicine, future holds great promise in improving the efficacy of immunotherapies and alleviating bladder cancer burden.

Statistical analysis plan for the LAST ACT clinical trial; a Leukotriene A4 hydrolase Stratified non-inferiority Trial of Adjunctive Corticosteroids for HIV-negative adults with Tuberculous meningitis

Tuberculous meningitis (TBM) is the most severe form of tuberculosis. Corticosteroids are currently recommended as an adjunctive therapy in HIV-negative adults with TBM. However, benefit from corticosteroids in TBM may depend upon host leukotriene A4 hydrolase (LTA4H) genotype and the corresponding inflammatory phenotypes. This article describes the planned analyses for the primary publication of the results of the LAST ACT clinical trial (NCT03100786): ‘Leukotriene A4 hydrolase Stratified Trial of Adjunctive Corticosteroids for HIV-negative adults with Tuberculous meningitis’. The primary hypothesis addressed by the trial is that LTA4H genotype, in particular CC or CT genotype, determines whether adjunctive dexamethasone benefits or harms adults with TBM. The trial was an LTA4H genotype stratified, parallel group, randomised, double blind, placebo-controlled multi-centre Phase III trial of dexamethasone given for 6–8 weeks in addition to standard anti-tuberculosis drugs. LTA4H genotype (CC, CT, TT) was determined in all participants prior to randomisation; only those with CC or CT genotype were randomised to dexamethasone or placebo. All TT genotype participants received dexamethasone because prior data indicated survival was increased by dexamethasone in this genotype. The primary endpoint was all-cause death or new neurological event over the first 12 months after randomisation. We took a hybrid trial-design approach which aims to prove non-inferiority of placebo first but also allows claiming superiority of placebo in case dexamethasone causes substantial harm. This statistical analysis plan expands upon and updates the analysis plan outlined in the published study protocol.

Salt Substitution and Recurrent Stroke and Death

The direct effect of consumption of salt substitutes on recurrent stroke and mortality among patients with stroke remains unclear. To evaluate the effects of salt substitutes vs regular salt on the incidence of recurrent stroke and mortality among patients with stroke. The Salt Substitute and Stroke Study (SSaSS), an open-label, cluster randomized clinical trial, was conducted in 600 northern Chinese villages (clusters). Patients who self-reported a hospital diagnosis of stroke were included in this prespecified subgroup analysis. Data were analyzed from November 2023 to August 2024. Participants were assigned to use either a salt substitute, consisting of 75% sodium chloride and 25% potassium chloride by mass, or regular salt. The primary outcome was recurrent stroke. After excluding 5746 persons without a baseline history of stroke, 15 249 patients with stroke (mean [SD] age, 64.1 [8.8] years; 6999 [45.9%] female; 8250 male [54.1%]) were included. Over a median (IQR) follow-up of 61.2 (60.9-61.6) months, the mean difference in systolic blood pressure was -2.05 mm Hg (95% CI, -3.03 to -1.08 mm Hg). A total of 2735 recurrent stroke events (691 fatal and 2044 nonfatal) and 3242 deaths were recorded. Recurrent stroke was significantly lower in the salt substitute vs regular salt group (rate ratio [RR], 0.86; 95% CI, 0.77-0.95; P = .005), with larger effects on hemorrhagic stroke (relative reduction, 30%; P = .002). Death rates were also significantly lower (RR, 0.88; 95% CI, 0.82-0.96; P = .003), with larger effects on stroke-related deaths (relative reduction 21%; P = .01). No significant difference was observed for hyperkalemia (RR, 1.01; 95% CI, 0.74-1.38; P = .96). Results of this cluster trial demonstrate that salt substitution was safe, along with reduced risks of stroke recurrence and death, which underscores large health gains from scaling up this low-cost intervention among patients with stroke. ClinicalTrials.gov Identifier: NCT02092090.