Developing a knowledge transfer and exchange strategy for a clinical trials unit.

Need For A Strategic Approach To Knowledge Transfer And Exchange: Late-phase clinical trials and systematic reviews find results that have the potential to improve health outcomes for people. However, there are often delays in these results influencing clinical practice. We developed a knowledge transfer and exchange strategy to support research teams, aiming to identify activities along the research process to maximise and accelerate the research impact.

Central statistical monitoring in clinical trial management: A scoping review.

Background: Clinical trials handle a huge amount of data which can be used during the trial to improve the ongoing study conduct. It is suggested by regulators to implement the remote approach to evaluate clinical trials by analysing collected data. Central statistical monitoring helps to achieve that by employing quantitative methods, the results of which are a basis for decision-making on quality issues.

Re-analysis of data from cluster randomised trials to explore the impact of model choice on estimates of odds ratios: study protocol.

Background: There are numerous approaches available to analyse data from cluster randomised trials. These include cluster-level summary methods and individual-level methods accounting for clustering, such as generalised estimating equations and generalised linear mixed models. There has been much methodological work showing that estimates of treatment effects can vary depending on the choice of approach, particularly when estimating odds ratios, essentially because the different approaches target different estimands.

Is inverse probability of censoring weighting a safer choice than per-protocol analysis in clinical trials?

Deviation from the treatment strategy under investigation occurs in many clinical trials. We term this intervention deviation. Per-protocol analyses are widely adopted to estimate a hypothetical estimand without the occurrence of intervention deviation.

Determining Targets for Antiretroviral Drug Concentrations: A Causal Framework Illustrated With Pediatric Efavirenz Data From the CHAPAS-3 Trial.

Background: Determining a therapeutic window for maintaining antiretroviral drug concentrations within an appropriate range is required for identifying effective dosing regimens. The limits of this window are typically calculated using predictive models. We propose that target concentrations should instead be calculated based on counterfactual probabilities of relevant outcomes and describe a counterfactual framework for this.

Cost-effectiveness of viral load testing for transitioning antiretroviral therapy-experienced children to dolutegravir in South Africa: a modelling analysis.

Background: For children with HIV on antiretroviral therapy (ART), transitioning to dolutegravir-containing regimens is recommended. The aim of this study was to assess whether introducing viral load testing to inform new nucleoside or nucleotide reverse transcriptase inhibitors (NRTIs) for children with HIV and viraemia alongside dolutegravir-based ART is beneficial and of good economic value.

Methods: We used the Cost-Effectiveness of Preventing AIDS Complications-Pediatric model to project clinical and cost implications of three strategies among a simulated cohort of South African children aged 8 years with HIV receiving abacavir-lamivudine-efavirenz: (1) continue current ART (no dolutegravir; abacavir-lamivudine-efavirenz); (2) transition all children with HIV to dolutegravir, keeping current NRTIs (dolutegravir; abacavir-lamivudine-dolutegravir); or (3) transition to dolutegravir based on viral load testing (viral load plus dolutegravir), keeping current NRTIs if virologically suppressed (abacavir-lamivudine-dolutegravir, 70% of cohort) or switching abacavir to zidovudine (zidovudine) if viraemic (zidovudine-lamivudine-dolutegravir, 30%).

Adapting the design of the ongoing RAMPART trial in response to external evidence: An example for trials which take many years to run and report.

Clinical trials to establish the efficacy of new agents in the adjuvant cancer setting typically take many years to complete. During that time, external factors can impact recruitment and reporting plans. An example is a new standard of care becoming available during the recruitment period.

Fraudulent Participation in Online Qualitative Studies: Practical Recommendations on an Emerging Phenomenon.

Fraudulent participation is defined in the following as participation in research by individuals who, for one reason or another, intentionally provide false responses. Qualitative studies are at an increased risk of fraudulent participation when online recruitment and participation are used, and monetary incentives offered. Fraudulent participation threatens data quality and subsequent evidence-based practice, yet validated guidance on how to tackle it is lacking.

Accounting for bias due to outcome data missing not at random: comparison and illustration of two approaches to probabilistic bias analysis: a simulation study.

Background: Bias from data missing not at random (MNAR) is a persistent concern in health-related research. A bias analysis quantitatively assesses how conclusions change under different assumptions about missingness using bias parameters that govern the magnitude and direction of the bias. Probabilistic bias analysis specifies a prior distribution for these parameters, explicitly incorporating available information and uncertainty about their true values.

A new trial monitoring plan (TMP) template for clinical trials: output from a Delphi process.

Background: Monitoring is a crucial part of trial conduct and ensures that participants' data is fairly represented, and future healthcare information is enhanced. This project aims to improve trial monitoring by creating a trial monitoring plan (TMP) template with input from individuals experienced in monitoring clinical trials.

Methods: A review of monitoring plans received from UK Clinical Research Collaboration (UKCRC) registered clinical trials units (CTU)s created the basis for a preliminary TMP template and a Delphi survey.

Safety, tolerability, and efficacy outcomes of the Investigation of Levetiracetam in Alzheimer's disease (ILiAD) study: a pilot, double-blind placebo-controlled crossover trial.

Objective: To assess whether the antiseizure medication levetiracetam may improve cognition in individuals with Alzheimer's disease who have not previously experienced a seizure.

Methods: We performed a randomized, double-blind, placebo-controlled crossover pilot study in individuals with mild-to-moderate Alzheimer's disease. Electroencephalography was performed at baseline and those with active epileptiform discharges were excluded.

Long-term efficacy and safety of two short standardised regimens for the treatment of rifampicin-resistant tuberculosis (STREAM stage 2): extended follow-up of an open-label, multicentre, randomised, non-inferiority trial.

Background: STREAM stage 2 showed that two bedaquiline-containing regimens (a 9-month all-oral regimen and a 6-month regimen with 8 weeks of aminoglycoside) had superior efficacy to a 9-month injectable-containing regimen for rifampicin-resistant tuberculosis up to 76 weeks after randomisation. Our objective in this follow-up analysis was to assess the durability of efficacy and safety, including mortality, at 132 weeks.

Methods: We report the long-term outcomes from STREAM stage 2, a randomised, phase 3 non-inferiority (10% margin) trial in participants (aged ≥15 years) with rifampicin-resistant tuberculosis without fluoroquinolone or aminoglycoside resistance at 13 clinical sites in seven countries (Ethiopia, Georgia, India, Moldova, Mongolia, South Africa, and Uganda).

Comparative Efficacy and Safety of Moxifloxacin and Levofloxacin in a Short Standardised Rifampicin Resistant TB Regimen: A STREAM 2 Secondary Analysis.

(1) Background: The World Health Organisation (WHO) categorises moxifloxacin and levofloxacin as Group A drugs, which should be prioritised in the treatment of rifampicin-resistant tuberculosis. We compare their relative efficacy and safety using data from the STREAM trial; (2) Methods: Marginal structural models were used to balance differences in the baseline characteristics of participants receiving the STREAM control regimen containing either moxifloxacin or levofloxacin as this was not a randomised comparison. The difference in proportions between regimens was estimated for favourable outcome, any grade 3/4 adverse event, QTcF increase to ≥500 ms, QTcF increase from baseline by at least 60 ms, and any grade 3/4 adverse event excluding QT events, using weighted analyses; (3) Results: In efficacy analyses ( = 123), the weighted risk difference (moxifloxacin-levofloxacin, wRD) for a favourable outcome was -0.

Demonstrating the data integrity of routinely collected healthcare systems data for clinical trials (DEDICaTe): A proof-of-concept study.

Healthcare systems data (also known as real-world or routinely collected health data) could transform the conduct of clinical trials. Demonstrating integrity and provenance of these data is critical for clinical trials, to enable their use where appropriate and avoid duplication using scarce trial resources. Building on previous work, this proof-of-concept study used a data intelligence tool, the "Central Metastore," to provide metadata and lineage information of nationally held data.

Economic Evaluation of Population-Based BRCA1 and BRCA2 Testing in Canada.

Importance: Population-based BRCA testing can identify many more BRCA carriers who will be missed by the current practice of BRCA testing based on family history (FH) and clinical criteria. These carriers can benefit from screening and prevention, potentially preventing many more breast and ovarian cancers and deaths than the current practice.

Objective: To estimate the incremental lifetime health outcomes, costs, and cost-effectiveness associated with population-based BRCA testing compared with FH-based testing in Canada.

Sodium-glucose co-transporter-2 inhibitors for hospitalised patients with COVID-19: a prospective meta-analysis of randomised trials.

Background: Sodium-glucose co-transporter-2 (SGLT2) inhibitors have been proposed as a potential treatment for adults hospitalised with COVID-19, due to their potential anti-inflammatory and endothelial protective effects. Published evidence from randomised control trials (RCTs) does not provide evidence of benefit. We aimed to estimate the effect of oral administration of SGLT2 inhibitors compared with usual care or placebo in adults hospitalised with COVID-19.

Randomised Trial of No, Short-term, or Long-term Androgen Deprivation Therapy with Postoperative Radiotherapy After Radical Prostatectomy: Results from the Three-way Comparison of RADICALS-HD (NCT00541047).

Background And Objective: The use and duration of androgen deprivation therapy (ADT) with postoperative radiotherapy (RT) have been uncertain. RADICALS-HD compared adding no ("None"), 6-months ("Short"), or 24-mo ("Long") ADT to study efficacy in the long term.

Methods: Participants with prostate cancer were indicated for postoperative RT and agreed randomisation between all durations.

Identification of a serum proteomic biomarker panel using diagnosis specific ensemble learning and symptoms for early pancreatic cancer detection.

Background: The grim (<10% 5-year) survival rates for pancreatic ductal adenocarcinoma (PDAC) are attributed to its complex intrinsic biology and most often late-stage detection. The overlap of symptoms with benign gastrointestinal conditions in early stage further complicates timely detection. The suboptimal diagnostic performance of carbohydrate antigen (CA) 19-9 and elevation in benign hyperbilirubinaemia undermine its reliability, leaving a notable absence of accurate diagnostic biomarkers.

Symptom-triggered testing detects early stage and low volume resectable advanced stage ovarian cancer.

Objective: Symptom-triggered testing for ovarian cancer was introduced to the UK whereby symptomatic women undergo an ultrasound scan and serum CA125, and are referred to hospital within 2 weeks if these are abnormal. The potential value of symptom-triggered testing in the detection of early-stage disease or low tumor burden remains unclear in women with high grade serous ovarian cancer. In this descriptive study, we report on the International Federation of Gynecology and Obstetrics (FIGO) stage, disease distribution, and complete cytoreduction rates in women presenting via the fast-track pathway and who were diagnosed with high grade serous ovarian cancer.

Proactive integrated consultation-liaison psychiatry and time spent in hospital by older medical inpatients in England (The HOME Study): a multicentre, parallel-group, randomised controlled trial.

Background: Older people admitted to hospital in an emergency often have prolonged inpatient stays that worsen their outcomes, increase health-care costs, and reduce bed availability. Growing evidence suggests that the biopsychosocial complexity of their problems, which include cognitive impairment, depression, anxiety, multiple medical illnesses, and care needs resulting from functional dependency, prolongs hospital stays by making medical treatment less efficient and the planning of post-discharge care more difficult. We aimed to assess the effects of enhancing older inpatients' care with Proactive Integrated Consultation-Liaison Psychiatry (PICLP) in The HOME Study.