Are estimands being correctly used? A review of UK research protocols.

Background: The use of estimands in clinical trials was formalised with the adoption of the final International Conference on Harmonisation E9 Addendum on Estimands and Sensitivity Analysis in Clinical Trials (ICH E9(R1) Addendum) in November 2019. The declared objective of the ICH E9(R1) Addendum is to bring clarity and transparency to the research question of interest. For this to be achieved, the estimand must be described in accordance with the requirements of the ICH E9(R1) Addendum so that the target treatment effect is clear to all stakeholders.

Pharmacokinetics of lopinavir/ritonavir in second-line treatment of children living with HIV in the CHAPAS-4 trial.

Objective: Lopinavir/ritonavir (LPV/r) remains a much-used drug combination for treatment of children with HIV, but pharmacokinetic data when the adult formulation (LPV/r 200/50 mg) is used for children weighing 25-34.9 kg, or when combined with tenofovir alafenamide/emtricitabine (TAF/FTC), is currently lacking.

Design: We aim to provide this data by an intensive LPV/r pharmacokinetic sub-study nested within the CHAPAS-4 trial (#ISRCTN22964075).

Factors Predictive of Early Discontinuation of Preventive Treatment in Children With Household Exposure to Multidrug-resistant Tuberculosis.

Background: The World Health Organization recommended levofloxacin for tuberculosis (TB) preventive treatment for child and adult contacts of multidrug-resistant TB.

Method: TB-CHAMP (ISRCTN92634082) was a double-blind community-based multisite randomized placebo-controlled trial assessing levofloxacin as preventive treatment in children with household exposure to adults with microbiologically confirmed multidrug-resistant TB in South Africa. Households were randomized 1:1 to 24 weeks of daily levofloxacin (adult scored 250-mg tablets) versus placebo.

Tumor transcriptome-wide expression classifiers predict treatment sensitivity in advanced prostate cancers.

Advanced prostate cancers respond to hormone therapy but outcomes vary and no predictive tests exist for informed treatment selection. To identify novel biomarker-treatment pairings, we examined associations between biological pathways and 14-year survival outcomes of patients randomized in practice-changing phase 3 trials (testing docetaxel or abiraterone). We included transcriptome-wide expression signatures and immunohistochemistry markers (Ki-67 and PTEN) on prostate tumors from 1,523 patients (832 metastatic).

Mechanical circulatory support for infarct-related cardiogenic shock: a systematic review, pairwise and network meta-analysis.

Aims: Mortality from cardiogenic shock complicating acute myocardial infarction (AMI-CS) remains high, despite the increasing mechanical circulatory support (MCS) use in clinical practice.

Methods And Results: We undertook a systematic review and meta-analysis of trials assessing MCS in adults with AMI-CS. We searched Medline, EMBASE, CENTRAL, Web of Science, and Scopus from inception to May 2024.

Preferences between three options for androgen deprivation therapy: a focus group study.

Objectives: Androgen deprivation therapy (ADT) forms the mainstay of treatment for advanced prostate cancer. Traditionally administered as a luteinising hormone-releasing hormone (LHRH) agonist depot injection, newer options for ADT include transdermal oestradiol patches (tE2) or oral LHRH antagonists. This study aimed to identify whether this is an important choice for men, which treatment men would choose if offered either LHRH agonist injections, tE2 patches or oral LHRH antagonists as ADT, and to explore the factors influencing this decision.

Prevalence and factors associated with violence against women who exchange sex for money in Gulu City, Northern Uganda: a cross-sectional study.

Background: Gender-based violence (GBV) is a public health concern disproportionately affecting female sex workers (FSWs) globally. We investigated the prevalence and factors associated with GBV against women engaged in sex work in Gulu City, Uganda.

Methods: In this community-based study, we included FSWs purposely selected from hotspots within Gulu City, Uganda, between February and April 2023.

Fracture-related hospitalisations in newly diagnosed high-risk localised or metastatic hormone-sensitive prostate cancer: secondary analysis of the STAMPEDE phase III trials of docetaxel and zoledronic acid using healthcare systems data.

Background: Androgen deprivation therapy (ADT), the mainstay systemic treatment for high risk non-metastatic (M0) and metastatic (M1) prostate cancer is associated with bone loss and increased fracture risk. The STAMPEDE trial tested the addition of zoledronic acid (ZA) ± docetaxel (with prednisolone) to ADT. Both regimens may impact bone health.

Dupilumab versus Lebrikizumab Demonstrates Greater Likelihood of Achieving and Maintaining Improvements in Efficacy Outcomes Using a Placebo-Adjusted Indirect Treatment Comparison.

Introduction: Dupilumab and lebrikizumab have demonstrated efficacy in atopic dermatitis (AD) clinical trials; however, no direct comparisons exist.

Methods: Efficacy outcome achievement (dupilumab and lebrikizumab with topical corticosteroids [TCS]) at 16 weeks and efficacy outcomes maintenance (dupilumab and lebrikizumab monotherapy without TCS) at 52 weeks were assessed using a placebo-adjusted Bucher indirect treatment comparison (ITC). Week 16 data were sourced from LIBERTY AD CHRONOS (dupilumab, n = 106; placebo, n = 315) and ADhere (lebrikizumab, n = 145; placebo, n = 66) trials.

Prospective multicentre randomised controlled trial to assess the clinical effectiveness of the novel CirrhoCare digital therapeutic management system: a study protocol.

Introduction: Liver cirrhosis accounts for over 10 000 deaths in the UK each year with a total loss of 60 000 quality-adjusted life-years. There is a substantial cost to the NHS of £4.5 billion, with new liver-related decompensation events accounting for the majority of this.

Neural networks to estimate multiple sclerosis disability and predict progression using routinely collected healthcare data.

Background And Objectives: Multiple sclerosis (MS)-related disability is conventionally measured using the Expanded Disability Status Scale (EDSS), which requires neurological examination and is generally embedded in clinical records, making it unavailable in administrative datasets. This limits its utility for population-level estimates and healthcare planning. This study aims to use routinely collected healthcare data to fill this gap.

Trial Analysis and Interpretation in Critical Care Using the Evidential (Likelihood) Approach: Rationale and Practical Considerations.

Selecting the optimal methodological framework for evidence synthesis presents a fundamental challenge in contemporary clinical research. In critical care, in which many interventions yield inconclusive results under traditional value-based analyses, complementary analytical approaches can enhance our understanding of trial data. Although frequentist statistics remain predominant and Bayesian methods have recently experienced a resurgence of interest, the evidential (or likelihood) framework offers a methodological perspective that potentially bridges these two inferential paradigms.

Duration of Androgen Suppression with Postoperative Radiotherapy (DADSPORT) for Nonmetastatic Prostate Cancer: A Collaborative Systematic Review and Meta-analysis of Aggregate Data.

Background And Objective: To better understand the role of hormone therapy (HT) with postoperative radiotherapy (RT) for nonmetastatic prostate cancer, the DADSPORT Collaboration planned a systematic review and meta-analysis of aggregate data from randomised controlled trials (RCTs).

Methods: RCTs evaluating HT with postoperative RT in people with nonmetastatic prostate cancer were identified. Methods were prespecified prior to results of recent trials being known (CRD42022325769).

Collaboration on the optimal timing of anticoagulation after ischaemic stroke and atrial fibrillation: a systematic review and prospective individual participant data meta-analysis of randomised controlled trials (CATALYST).

Background: The optimal timing of oral anticoagulation for prevention of early ischaemic stroke recurrence in people with acute ischaemic stroke and atrial fibrillation remains uncertain. We aimed to estimate the effects of starting a direct oral anticoagulant (DOAC) early (≤4 days) versus later (≥5 days) after onset of ischaemic stroke.

Methods: For this systematic review and meta-analysis we searched the electronic databases PubMed, Cochrane Central Register of Controlled Trials, and Embase for randomised controlled trials published from inception until March 16, 2025.

Spatiotemporal effects on dengue incidence based on a large cluster randomized study.

A recent large-scale cluster randomized test-negative study assessed the impact of a mosquito-based intervention on the incidence of clinical dengue showing a protective efficacy of 77.1% (95% CI: (65.3%, 84.

External validation of the LENT and PROMISE prognostic scores for malignant pleural effusion.

Background: Accurate survival estimation in malignant pleural effusion is essential to guide clinical management strategies and inform patient discussion. The LENT and PROMISE scores were developed to aid prognostication in malignant pleural effusion; however their uptake in practice has been limited. We aimed to conduct a detailed external validation of the LENT and PROMISE scores to develop recommendations regarding clinical utility, and to highlight factors limiting performance.

Pharmacokinetic data of atazanavir/ritonavir in second-line treatment of children living with HIV.

Background: There are limited data on the pharmacokinetics of atazanavir/ritonavir (ATV/r) in children living with HIV, and no data when combined with emtricitabine/tenofovir alafenamide. Here were present the results of an intensive pharmacokinetic sub-study nested within the CHAPAS-4 trial (ISRCTN22964075), to evaluate ATV/r exposure in children.

Methods: Children aged 3 - 15 years, weighing 14 - 24.

Agreement and utility of coded primary and secondary care data for long-term follow-up of clinical trial outcomes.

Background: Whilst interest in efficient trial design has grown with the use of electronic health records (EHRs) to collect trial outcomes, practical challenges remain. Commonly raised concerns often revolve around data availability, data quality and issues with data validation. This study aimed to assess the agreement between data collected on clinical trial participants from different sources to provide empirical evidence on the utility of EHRs for follow-up in randomised controlled trials (RCTs).

External validation of a digital pathology-based multimodal artificial intelligence-derived prognostic model in patients with advanced prostate cancer starting long-term androgen deprivation therapy: a post-hoc ancillary biomarker study of four phase 3 randomised controlled trials of the STAMPEDE platform protocol.

Background: Effective prognostication improves selection of patients with prostate cancer for treatment combinations. We aimed to evaluate whether a previously developed multimodal artificial intelligence (MMAI) algorithm was prognostic in very advanced prostate cancer using data from four phase 3 trials of the STAMPEDE platform protocol.

Methods: We included patients starting androgen-deprivation therapy in the docetaxel, docetaxel plus zoledronic acid, abiraterone, or abiraterone plus enzalutamide trials.

Risk of tuberculosis infection in young children exposed to multidrug-resistant tuberculosis in the TB-CHAMP multi-site randomised controlled trial.

Background: Young children have a high risk of developing tuberculosis (TB) disease following infection with Mycobacterium tuberculosis (M.tb) in the absence of preventive treatment. Infection prevalence and risk factors for infection impact delivery of prevention strategies.

Summary measures in non-inferiority clinical trials with a time-to-event outcome: an empirical comparison of power.

Background: Time-to-event data is commonly used in non-inferiority clinical trials. While the hazard ratio is a popular summary measure in this context, the difference in restricted mean survival time has been theoretically shown to increase power and interpretability. This study aimed to empirically compare the power of the hazard ratio, difference in survival and difference in restricted mean survival time for non-inferiority clinical trials with a time-to-event outcome recently published in key clinical journals.

Anticoagulation Timing in Acute Stroke With Atrial Fibrillation According to Chronic Kidney Disease: The OPTIMAS Trial.

Background: Patients with chronic kidney disease (CKD) are at increased risk of ischemic stroke (IS) and intracerebral hemorrhage, so the safety and efficacy of early direct oral anticoagulant (DOAC) initiation in those with CKD are of clinical relevance.

Methods: OPTIMAS (Optimal Timing of Anticoagulation After Acute Ischemic Stroke With Atrial Fibrillation) was a multicenter, randomized, parallel-group, open-label trial with blinded outcome assessment, recruiting patients with IS and atrial fibrillation from 100 UK hospitals between 2019 and 2024. Participants were randomized 1:1, stratified by stroke severity, to early (within 4 days of onset) or delayed (at days 7-14) DOAC initiation.