Enhanced patient counselling and SMS reminder messages to improve access to community-based eye care services in Meru, Kenya: an embedded, pragmatic, individual-level, randomised, controlled, adaptive platform trial.

Genetic deficiency of factor XI is associated with a reduced risk of ischemic stroke. Asundexian is a direct inhibitor of activated factor XIa (FXIa) with a low risk of bleeding in early trials. We seek to determine its efficacy and safety combined with antiplatelet therapy for prevention of ischemic stroke. Oral faCtor Eleven A iNhibitor asundexian as novel antithrombotiC (OCEANIC-STROKE) is a placebo-controlled, double-blind, event-driven randomised trial including participants with stroke (NIHSS ≤ 15) or high-risk TIA (ABCD2 6 or 7) within 72h of onset. Participants had at least one of the following: atherosclerosis of extra- or intracranial vessels, a medical history of atherosclerosis or an imaged acute non-lacunar infarct. We excluded sources of stroke requiring anticoagulation and active non-trivial bleeding other than hemorrhagic infarction (HI 1 or 2). Participants received asundexian 50mg daily or placebo stratified by planned concurrent antiplatelet therapy (single vs dual). The primary endpoint is time to ischemic stroke. We present baseline characteristics as of 5 June 2025. Between January 2023 and February 2025, we randomised 12,327 participants. Participants were 67% male with a mean (SD) age of 68 (11) years. Ischemic stroke was the index event for 95% of whom 27.4% had thrombolysis and/or mechanical thrombectomy. By TOAST classification, 43% of index strokes were LAA, 22% small vessel disease, 30% undetermined and 2% cardioembolic. Dual antiplatelets were planned in 63% as standard initial treatment. Trial completion is anticipated in October 2025. OCEANIC-STROKE will be the first completed trial of FXIa inhibition for prevention of stroke after non-cardioembolic stroke or TIA. ClinicalTrials.gov (NCT05686070).

Prostate cancer (PCa) bone lesions are bone-forming, which contribute to an immunosuppressive bone-tumor microenvironment (bone-TME). Targeting PCa-induced bone with the radiopharmaceutical Radium-223 (Ra223) is approved for men with bone-metastatic castration-resistant PCa (bmCRPC). We studied the effect of Ra223 on spatial localization of tumor and immune cells in bmCRPC tumor biopsies to gain insights into therapeutic immunomodulation of the bone-TME. Transiliac bone marrow biopsies were performed at baseline and end of treatment (EOT) in 24 patients with bmCRPC treated with Ra223. In three patients with paired specimens containing tumor, multiplex immunofluorescence was performed with antibodies for a tumor cell marker (CK), T-cell markers (CD3, CD4, CD8, FOXP3, and granzyme B), macrophage markers (CD68 [total macrophages] and CD206 [M2-like macrophages]). In all three patients, we observed enrichment of CD68+ macrophages, around tumor-induced bone at baseline. CD3 staining revealed T cell depletion where tumor cells formed large sheets but not where tumor cells were scattered. The effects of Ra223 on tumor cells and T cell subsets were heterogeneous. In one patient, tumor cells were reduced, and CD3+/CD8+ T cells were increased. In a second patient who evidenced osteolytic progression, tumor cells were increased while CD3+/CD8+ T cells were decreased. In a third patient, there was high number of tumor cells at baseline that modestly decreased and the number of CD3+/CD8+ T cells modestly increased after Ra223 treatment. The changes in tumor cell numbers after Ra223 treatment seemed to be inversely correlated with changes in CD3+/CD8+ and CD4+/FoxP3+ cells, but not with other immune cells, in these 3 patients. Further characterization of immune cells in the bone-TME will be required before developing strategies to enhance immunotherapy efficacy in bmCRPC. This study does not report the clinical results of a clinical trial, but it does use samples from a completed clinical trial that is registered with clinicaltrials.gov (NCT02135484).

Ibudilast attenuates the association between pain intensity and heavy drinking in alcohol use disorder: A secondary analysis of a randomized clinical trial.

A parallel randomized trial is frequently used to investigate the treatment effectiveness as compared to the gold standard. In early phase trials, a group sequential design has the potential to reduce the expected sample size as compared to the traditional one-stage design, and protect participants when a new treatment is not as effective as expected. When the outcome is binary, a group sequential design based on exact binomial distribution is preferable as compared to the asymptotic limiting distribution. To improve the design efficiency, we propose to develop new parallel two-stage adaptive design and promising zone design allowing sample size adjustment in the second stage based on the outcome from the first stage. The conditional probability is guaranteed in the proposed designs when a trial proceeds to the second stage. All these designs control the type I error rate, but only the proposed two designs guarantee the conditional probability constraint. We used a real example from a completed cancer trial to illustrate the application of the proposed designs. The adaptive designsubstantially increases unconditional power but requires a large sample size as compared to the group sequential design. The promising zone design achieves a good balance between statistical power and the expected sample size.

BackgroundDysregulated endocannabinoid signaling is involved in Fragile X syndrome (FXS), suggesting a potential role for the endocannabinoid signaling modulator, cannabidiol, in treatment. ZYN002 is a synthetic cannabidiol that has been uniquely formulated as a gel for transdermal delivery and is currently under investigation for the treatment of behavioral symptoms associated with FXS. DesignZYN2-CL-017 is an ongoing, long-term, open-label extension (OLE) safety trial of ZYN002 in patients with FXS. We are enrolling patients from past and current ZYN002 clinical trials to evaluate the safety and tolerability of ZYN002 in patients with FXS. MethodsPrimary safety assessments were conducted in patients who enrolled into the OLE from 2 completed ZYN002 trials. Secondary analyses, conducted in a subgroup enrolled from a completed placebo-controlled trial of ZYN002, included the FXS-specific Aberrant Behavior Checklist-Community Social Avoidance and Irritability subscales (ABC-CFXS SA and ABC-CFXS Irr, examined change from baseline of the randomized study) and the Caregiver Global Impression of Change (CaGI-C, examined change from baseline of the OLE), in which caregivers were asked to rate the change in their child’s overall behavior.ResultsAt the time of this interim analysis data cut (January 31, 2024), 240 patients had been enrolled from 2 completed ZYN002 trials. Mean age at entry to the OLE was 9.7 years (range 3-17 years), and the majority were male (76.3%) and White (80.4%). Mean exposure to ZYN002 during the initial trials and OLE was 28 months. Treatment-related adverse events (AEs) were reported in 12.9% of patients; the most common (6.7% of patients) was short-term application site pain. The highest degree of skin irritation reported by investigators was moderate erythema in 7 patients (2.9%). In the secondary analysis cohort (n=196 evaluable patients), patients demonstrated clinically meaningful changes in ABC-CFXS SA, ABC-CFXS Irr, and CaGI-C scores. ConclusionsInterim analysis results of the ongoing OLE in children, adolescents, and young adults with FXS demonstrated that ZYN002 has a favorable long-term safety profile and is generally well tolerated. Clinically meaningful changes in behaviors from baseline continued to be observed during the OLE. These findings support further study of ZYN002 in patients with FXS. Trial registrationZYN2-CL-017 is registered on Clinicaltrials.gov (NCT03802799) on December 26, 2018.

Background Millions of people each year suffer from chronic low back pain (cLBP), which adversely affects their physical and mental health. While non-pharmacological interventions such as mindfulness are known to be effective in treating cLBP, not all patients experience the same benefit. Determining who these treatments might work best for is difficult, as there are no reliable predictors of the response to mindfulness for cLBP. The objective of the current study was to apply predictive machine learning to data collected from a completed clinical trial of mindfulness for cLBP to identify phenotypes characterizing those who did and did not respond to the intervention. Methods The analyses here focused on 132 participants in the intervention arm of the clinical trial of mindfulness for cLBP. The Random Forest machine learning technique was used to identify key characteristics of responders (49) and non-responders (83). Results The top three responder phenotypes were able to identify 26 out of the 49 responders with 92%–100% precision. The top three non-responder phenotypes were able to identify 36 out of 83 non-responders, all with 100% precision. Conclusions Results from this machine learning based phenotyping can guide clinician and patient decision-making to maximize clinical efficiency, patient outcomes, and resource use as well as inform research and development of mindfulness-based treatments for pain.

Long-term follow-up demonstrates durable clinical benefits of exagamglogene autotemcel for sickle cell disease with recurrent vaso-occlusive crises: Final results of climb SCD-121

End-of-study analysis of the HOPE-B trial confirms the durable efficacy and safety of etranacogene dezaparvovec hemophilia b gene therapy over 5 years

The high placebo responses observed in many placebo-controlled randomized clinical trials, particularly in psychiatric research, have hindered the demonstration of treatment efficacy. To address this issue, Fava proposed the Sequential Parallel Comparison Design (SPCD) in 2003, which aims to mitigate the placebo response by estimating a pooled treatment effect (denoted by ). This is achieved by combining the treatment effect observed in the first stage among intention-to-treat (ITT) subjects with the second-stage treatment effect among placebo non-responders through a weighted average approach. However, the challenges in interpreting this pooled treatment effect causally complicate the review of SPCD-designed studies. This paper explored the pooled SPCD treatment effect and contrasted it with two causal estimators: The causal average treatment effect among non-responders (denoted by ) and the causal average treatment effect had all ITT subjects exhibited low responses during the study (denoted by ). These estimators reflect two opposing views of the placebo response, either as an immutable personal trait or as a manipulable feature. Through carefully designed simulation studies, we demonstrated the direction and magnitude of bias when interpreting as either or . In these simulation studies, tends to underestimate the treatment benefit when compared to two causal estimators in most scenarios. Furthermore, , developed to overcome the interpretational limitations of , exhibits statistically superior performance over and in terms of bias and MSE when using the G-formula approach. As such, we recommend its adoption where applicable. The first completed trial using the SPCD design, ADAPT-A, is reanalyzed to further confirm these findings.

BackgroundSuccessfully completing clinical trials for rare and heterogeneous disorders, like spinal cord injuries (SCI), remains challenging, thereby reducing the ability to test and translate promising preclinical findings. We propose synthetic controls, derived from data-driven predictions of recovery in patients undergoing standard treatments, to mitigate these challenges, in particular related to patient recruitment.MethodsBased on data from the European Multicenter Study about Spinal Cord Injury (EMSCI) and the Sygen trial, we construct synthetic controls from personalized predictions of neurological recovery of sequences of segmental motor scores. A total of six architectures (linear, tree, and deep learning models) are compared. We demonstrate the applicability of synthetic controls through a simulation framework modeling the randomization process in a clinical trial and a case study that re-evaluates the recently completed Nogo Inhibition in SCI (NISCI) trial as a single-arm trial post hoc.ResultsThe primary dataset included 4196 patients from EMSCI and 587 patients from the Sygen trial for external validation. We identified a convolutional neural network as the best-performing architecture to predict segmental motor score sequences, achieving a median root mean squared error below the neurological level of injury of 0.55. Our trial simulations demonstrate that synthetic controls are a viable alternative to randomization, as the proposed solution reduces intercohort heterogeneity and leads to no significant differences with randomized controls in our case study reassessing a clinical trial.ConclusionsWe provide a comprehensive benchmark of data-driven prediction architectures for neurological recovery after SCI. Apart from offering individual patients a specific recovery prediction, these models constitute the basis for synthetic controls. Using real-world data from a completed trial in SCI, we show that synthetic controls could mitigate the challenges of small cohorts and patient recruitment in rare disorders, offering the opportunity to maximize the number of patients receiving an investigative treatment.GitHub repositoryhttps://gitlab.ethz.ch/BMDSlab/publications/sci/sci-in-silico-trials.Supplementary InformationThe online version contains supplementary material available at 10.1186/s12916-025-04405-3.

Efficacy and safety of tirzepatide in children and adolescents with type 2 diabetes (SURPASS-PEDS): a randomised, double-blind, placebo-controlled, phase 3 trial.

Radiation Doses to Cardiac Substructures Predict Elevation in High-sensitivity Cardiac Troponin T Levels in Radiation Therapy for Lung Cancer.

Pharmacogenetics of steady-state metabolism, pharmacokinetics, and adverse effects of voriconazole in healthy participants.

Background: Fecal microbiota, live-jslm (RBL) is a microbiota-based product for the prevention of recurrent Clostridioides difficile infection (rCDI) in adults following antibiotic treatment. The safety and clinical effectiveness of RBL administered via colonoscopy in adults with rCDI were evaluated in CDI-SCOPE. An 8-week analysis showed 9.8% of participants had RBL-related treatment-emergent adverse events (TEAEs; primary endpoint) and 95.1% experienced treatment success (no CDI recurrence). Objectives: To evaluate long-term safety and clinical effectiveness of RBL through 6 months of follow-up in CDI-SCOPE. Design: Single-arm exploratory phase IIIb trial conducted at 12 sites in the United States. Methods: Eligible adults with rCDI received a single 150-mL dose of RBL to the right colon via colonoscopy. The primary endpoint was RBL-related TEAEs through 8 weeks after RBL administration or confirmed treatment failure. Secondary endpoints included safety up to 6 months after RBL administration. Exploratory analyses included assessment of further CDI episodes. Results: Of the 41 participants enrolled, 39 completed trial assessments through 6 months. From 8 weeks through 6 months after RBL administration, 36 TEAEs in 15 participants (36.6%) were reported, one of which (irritable bowel syndrome) was RBL-related; most TEAEs (97.2%) were of mild or moderate severity. Over the 6-month trial period, 23 participants (56.1%) experienced 69 TEAEs; 94.2% were of mild or moderate severity. Serious TEAEs occurred in three participants (7.3%), none of which were related to RBL or its administration, and no TEAEs led to discontinuation or death. Overall, 38 participants (92.7%) did not experience further CDI episodes, 1 (2.4%) did between 8 weeks and 6 months, and 2 (4.9%) had an indeterminate outcome due to trial withdrawal before 8 weeks. Conclusion: RBL administered via colonoscopy was safe and effective for preventing CDI recurrence in adults with rCDI in CDI-SCOPE. Trial registration: ClinicalTrials.gov: NCT05831189.

Kinesthetic motor imagery (KMI), the mental rehearsal of a motor task without its actual performance, constitutes one of the most common techniques used for brain–computer interface (BCI) control for movement-related tasks. The effect of neural injury on motor cortical activity during execution and imagery remains under investigation in terms of activations, processing of motor onset, and BCI control. The current work aims to conduct a post hoc investigation of the event-related potential (ERP)-based processing of KMI during BCI control of anthropomorphic robotic arms by spinal cord injury (SCI) patients and healthy control participants in a completed clinical trial. For this purpose, we analyzed 14-channel electroencephalography (EEG) data from 10 patients with cervical SCI and 8 healthy individuals, recorded through Emotiv EPOC BCI, as the participants attempted to move anthropomorphic robotic arms using KMI. EEG data were pre-processed by band-pass filtering (8–30 Hz) and independent component analysis (ICA). ERPs were calculated at the sensor space, and analysis of variance (ANOVA) was used to determine potential differences between groups. Our results showed no statistically significant differences between SCI patients and healthy control groups regarding mean amplitude and latency (p < 0.05) across the recorded channels at various time points during stimulus presentation. Notably, no significant differences were observed in ERP components, except for the P200 component at the T8 channel. These findings suggest that brain circuits associated with motor planning and sensorimotor processes are not disrupted due to anatomical damage following SCI. The temporal dynamics of motor-related areas—particularly in channels like F3, FC5, and F7—indicate that essential motor imagery (MI) circuits remain functional. Limitations include the relatively small sample size that may hamper the generalization of our findings, the sensor-space analysis that restricts anatomical specificity and neurophysiological interpretations, and the use of a low-density EEG headset, lacking coverage over key motor regions. Non-invasive EEG-based BCI systems for motor rehabilitation in SCI patients could effectively leverage intact neural circuits to promote neuroplasticity and facilitate motor recovery. Future work should include validation against larger, longitudinal, high-density, source-space EEG datasets.

Effects of retatrutide on body composition in people with type 2 diabetes: a substudy of a phase 2, double-blind, parallel-group, placebo-controlled, randomised trial.

Efficacy and safety of ervogastat alone and in combination with clesacostat in patients with biopsy-confirmed metabolic dysfunction-associated steatohepatitis and F2-F3 fibrosis (MIRNA): results from a phase 2, randomised, double-blind, double-dummy study.

Prademagene zamikeracel for recessive dystrophic epidermolysis bullosa wounds (VIITAL): a two-centre, randomised, open-label, intrapatient-controlled phase 3 trial.

Abstract Objective: Data on prognostication of Asian HR+/HER2/neu- early stage breast cancer patients using Western prognostic tests is limited and intriguing. Asian patients do get diagnosed almost a decade earlier and typically in Stage II thus the underlying tumor biology could be different. CanAssist Breast (CAB)- an immunohistochemistry and artificial intelligence based prognostic test was developed on Indian patient’s tumors and validated in retrospective global studies in India, US, Spain, Germany, Austria, Italy and via prospective-randomized completed TEAM trial in The Netherlands. CAB is included in Asian geriatric Society’s guidelines as well. Since mid 2016, CAB is in clinical use in India as well as Sri Lanka, Bangladesh, UAE and Turkey. In this abstract we assess the usefulness of CAB in our day to day treatment planning in India. Methods: We analysed use of CAB on total 643 consecutive patients in our clinical practice from mid 2016 till December 2023. Specifically, we analyzed how does CAB segregate patients under/over 48 years ie pre/post-menopausal, N0, N1 patients. Patients with varying levels of tumor size, tumor grade and expression of ER and PR. Results: Over all CAB segregated 66% patients as ‘low risk’ and 34% as ‘high risk’ for distant recurrence. Median age of the patient was 58 years and median tumor size was 2.5cm. Majority (75%) of patients were over 48 years of age. The low:high risk segregation in pre and post-menopausal was similar at 68:32 and 65:35. The current data is represented from North, South and West of India and in each of the regions as well the distribution of low:high risk proportions was similar. 33% patients had T1 tumors, 63% had T2 tumors however the low: high risk proportions in T1 versus T2 were significantly different at 84:16 and 59:41 respectively. Majority (75%) of patients had lymph node negative disease (N0) and the low:high risk proportions were 75:25 and 35:65 in N0 and lymph node positive (N1) disease. G1 tumors represented 12% of the total while 64% were G2 and 24% had G3 tumors. Low risk percentage across the three tumor grades was significantly different at 92%, 77% and 24% respectively. 88% of patients had ER and PR positive disease while 5% had ER+/PR- disease and for 7% PR status was unknown. 88% of patients had high ER expression (>70%) while 10% had intermediate (10-70%) and 1% had low ER (1-9%) expression. 46% patients had T2N0, 27% had T1N0, 7% had T1N1 and 17% had T2N1 disease. 99% were HER2/neu negative. CAB was used to plan treatment for all of these patients. We have treatment details for 77% of the patients. 94% of low risk patients did not get chemotherapy and 84% of high risk patients got chemotherapy. For the 6% low-risk patients who got chemotherapy, we believe the potential reasons could be N1 disease, G3 disease, high Ki67 index, Her2+ disease and pre-menopausal patients. Conclusion: CAB is able to segregate the patients into low or high risk in line with clinical parameters. CAB has helped 94% of low-risk patients to avoid chemotherapy. CAB represents tumor biology of younger patients and coupled with world-wide validation it presents as a cost-effective, ideal alternative to western prognostic tests to patients in Asia. Citation Format: Somashekhar, Rajiv Kumar, D. G. Vijay, Praveen Dadireddy, Shekhar Patil, Rohan Khandelwal, Mandeep Singh, Garima Dagga. Real world data on breast cancer prognostication in India using CanAssist Breast- an indigenous test validated in global studies [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P4-11-11.