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.

Lessons from the European Mpox Outbreak: Strengthening Cohort Research for Future Pandemic Preparedness.

Background: Well-designed cohort studies are crucial for pandemic preparedness informing evidence-based infection prevention and treatment strategies.

Objectives: Following the 2022 mpox outbreak in Europe, this scoping review critically evaluates the design, implementation, and characteristics of cohort studies focusing on mpox. The aim is to inform recommendations for the Cohort Coordination Board and CoMeCT to enhance cohort study research and improve preparedness.

Evaluating surrogates for overall survival in the adjuvant treatment of bladder cancer with chemotherapy.

Introduction: Surrogates for overall survival (OS) can expedite the development of adjuvant treatments for bladder cancer. We evaluated whether disease-free survival (DFS) or distant metastasis-free survival (DMFS) are valid surrogates for OS in patients with muscle-invasive disease treated with cisplatin-based chemotherapy after radical cystectomy.

Methods: We analyzed individual patient data from 1075 patients enrolled in 9 randomized controlled trials (RCTs) identified by systematic review.

Subjective Assessment of Eight CT Features in the Prediction of Dysthyroid Optic Neuropathy.

Purpose: To evaluate the subjective assessment of 8 orbital CT features for predicting dysthyroid optic neuropathy (DON).

Methods: Scan montages from 137 orbits without DON and 121 with DON were each graded independently by 3 observers for 8 imaging features: namely, degree of apical crowding, extraocular muscle enlargement, expansion of orbital fat, clarity of the superior orbital fissure, fat prolapse through the superior orbital fissure, medial wall bowing, general orbital vascular congestion, and dilation of the superior ophthalmic vein. Gradings were analyzed individually and also averaged across observers.

Confidence Intervals for Adaptive Trial Designs II: Case Study and Practical Guidance.

In adaptive clinical trials, the conventional confidence interval (CI) for a treatment effect is prone to undesirable properties such as undercoverage and potential inconsistency with the final hypothesis testing decision. Accordingly, as is stated in recent regulatory guidance on adaptive designs, there is the need for caution in the interpretation of CIs constructed during and after an adaptive clinical trial. However, it may be unclear which of the available CIs in the literature are preferable.

Confidence Intervals for Adaptive Trial Designs I: A Methodological Review.

Regulatory guidance notes the need for caution in the interpretation of confidence intervals (CIs) constructed during and after an adaptive clinical trial. Conventional CIs of the treatment effects are prone to undercoverage (as well as other undesirable properties) in many adaptive designs (ADs) because they do not take into account the potential and realized trial adaptations. This paper is the first in a two-part series that explores CIs for adaptive trials.

Tackling control risk problems in non-inferiority trials.

Non-inferiority trials aim to show that major disease related outcomes with a new intervention are not importantly worse than with standard care. These trials are useful when the new intervention has some advantages over standard care (eg, toxicity, convenience, or cost). The ability to show non-inferiority, however, is sensitive to the control risk, the outcome frequency under standard care.

Determining the Impact of Histology on the Incidence, Pattern, and Timing of Recurrences in Patients with Renal Cell Carcinoma: A Pooled Analysis from the SORCE and ASSURE Trials.

Background And Objective: Outcomes after nephrectomy for intermediate- and high-risk renal cell carcinoma (RCC) according to histological subtype are poorly characterised. This study aims to determine the value of RCC histology in predicting survival and to inform on surveillance strategies in relation to patterns of first recurrence.

Methods: We pooled data from phase 3 trials: SORCE ( = 1689) and ASSURE ( = 1853).

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.

Multiple Imputation of Missing Covariates When Using the Fine-Gray Model.

The Fine-Gray model for the subdistribution hazard is commonly used for estimating associations between covariates and competing risks outcomes. When there are missing values in the covariates included in a given model, researchers may wish to multiply impute them. Assuming interest lies in estimating the risk of only one of the competing events, this paper develops a substantive-model-compatible multiple imputation approach that exploits the parallels between the Fine-Gray model and the standard (single-event) Cox model.

Policies, practices, opportunities and challenges for tuberculosis screening: a global survey of national tuberculosis programmes.

Introduction: There are limited published data on how countries carry out screening for tuberculosis (TB) disease and what the perceived challenges are for implementing screening from a country perspective. Understanding these factors are important to enable better planning and support for the roll-out of appropriate screening interventions.

Methods: We conducted a cross-sectional survey of national TB programmes from countries reporting >1000 TB cases annually.

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.

Designing a response-over-continuous-intervention (ROCI) randomised trial: Implementation in the Phase 2C part (duration ranging) of the PARADIGM4TB trial.

Background/aims: Treatments for tuberculosis (TB) are often long and complicated. Standard 2-arm non-inferiority trials have been used to evaluate shorter durations of treatment regimens. The new response-over-continuous-intervention (ROCI) trial design has recently been proposed as a practical alternative for optimising some continuous aspect (e.

Development of a consensus extension of the estimands framework for cluster randomised trials (CRT-estimands): results from an international Delphi study.

Background: Estimands are increasingly used in randomised trials to clarify research objectives. The ICH E9(R1) addendum sets out five attributes necessary to describe a well-defined estimand. However, the addendum was primarily developed for individually randomised trials.

Platform trials-an emerging methodology for perioperative medicine: a narrative review.

The traditional model for testing new treatments, before widespread usage in clinical practice, is the parallel group randomised trial. However, these are often inefficient, time-consuming and expensive, which can be barriers to the timely improvement of clinical care. This is a particular issue for anaesthesia and perioperative medicine where funding for large clinical trials is often scarce.

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).

Outcome measures for randomised clinical trials and multicentre observational studies of cardiovascular diseases published in major clinical journals: systematic review and evidence mapping.

Background: Outcome measure choice and definition can determine the result of the study. We describe outcome measures and their definitions for cardiovascular studies in highly cited medical journals.

Methods: Cardiovascular phase III or IV randomised clinical trials (RCTs) or multicentre observational studies published in the , or between 1 January 2013 and 6 June 2024 from Embase and Ovid Medline were included.

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).

Prostate Pathway Embedded Comparative Trial: Outcomes from the Pilot Phase of the Imperial Prostate 3-PROState Pathway Embedded Comparative Trial.

Background And Objective: Rapid innovations in prostate cancer diagnosis and treatment have led to the adoption of innovative trial designs. The Imperial Prostate 3-PROState Pathway Embedded Comparative Trial (IP3-PROSPECT) aims to explore the feasibility and acceptability of a cohort multiple randomised controlled trial (cmRCT) design within the prostate cancer pathway.

Methods: Eligible participants were approached at the point of referral for a clinical suspicion of prostate cancer and were invited to join the cohort, agreeing in principle to future randomisations, without knowledge of the details of those interventions.

Proteomic and Genetic predictors and risk scores of cardiovascular diseases in persons living with HIV.

Background: Cardiovascular diseases (CVD) prediction models for persons living with HIV (PLWH) depend on traditional CVD risk factors, but these underestimate true risk. We aimed to identify proteins and genetic variants and create proteo-genomic risk scores for CVD in PLWH.

Methods: We analyzed genetic and protein data from participants involved in trials for PLWH.

Advancing Cervical Cancer Prevention Equity: Innovations in Self-Sampling and Digital Health Technologies Across Healthcare Settings.

Cervical cancer causes 350,000 deaths annually, with 90% occurring in low- and middle-income countries (LMICs), despite being largely preventable through vaccination and screening. This review examines innovative approaches to address screening coverage gaps worldwide, analysing both established programmes in high-income countries and implementation strategies for LMICs. Self-sampling technologies demonstrate significant potential to improve the uptake of cervical screening, thereby improving cervical cancer prevention compared to traditional methods, particularly benefiting underserved populations across all healthcare settings.

Assessing the feasibility and impact of clinical trial trustworthiness checks via an application to Cochrane Reviews: Stage 2 of the INSPECT-SR project.

Background And Objectives: The aim of the INveStigating ProblEmatic Clinical Trials in Systematic Reviews (INSPECT-SR) project is to develop a tool to identify problematic RCTs in systematic reviews. In stage 1 of the project, a list of potential trustworthiness checks was created. The checks on this list must be evaluated to determine which should be included in the INSPECT-SR tool.

Master protocol for a series of cohort-based randomized controlled trials to test tools to communicate research results to study participants and others with relevant lived experience: the SPIN-CLEAR Trials.

Background: Research results are often not communicated to study participants or others with relevant lived experience. Effective communication of research results would help study participants understand their contribution to research and could improve trust in research and likelihood of research participation. Few randomized controlled trials (RCTs), however, have compared the effectiveness of research communication tools, and it is not known which tools work best for different people.

Assessment of the steady-state drug-drug interactions between dolutegravir and ritonavir-boosted darunavir in adolescents.

Objectives: DTG is primarily metabolized by the UDP-glycosyltransferase (UGT) 1A1, and to a lesser extent by the cytochrome P450 (CYP) 3A4. Co-administration of DRV/r has been reported to decrease DTG plasma concentrations. Our aim was to distinguish the extent of the drug-drug interactions between DRV/r and DTG, and to evaluate the consequences of this interaction, in adolescents at steady state.