The use of linked administrative data in Australian randomised controlled trials: A scoping review.

BACKGROUND/AIMS: The demand for simplified data collection within trials to increase efficiency and reduce costs has led to broader interest in repurposing routinely collected administrative data for use in clinical trials research. The aim of this scoping review is to describe how and why administrative data have been used in Australian randomised controlled trial conduct and analyses, specifically the advantages and limitations of their use as well as barriers and enablers to accessing administrative data for use alongside randomised controlled trials. METHODS: Databases were searched to November 2022. Randomised controlled trials were included if they accessed one or more Australian administrative data sets, where some or all trial participants were enrolled in Australia, and where the article was published between January 2000 and November 2022. Titles and abstracts were independently screened by two reviewers, and the full texts of selected studies were assessed against the eligibility criteria by two independent reviewers. Data were extracted from included articles by two reviewers using a data extraction tool. RESULTS: Forty-one articles from 36 randomised controlled trials were included. Trial characteristics, including the sample size, disease area, population, and intervention, were varied; however, randomised controlled trials most commonly linked to government reimbursed claims data sets, hospital admissions data sets and birth/death registries, and the most common reason for linkage was to ascertain disease outcomes or survival status, and to track health service use. The majority of randomised controlled trials were able to achieve linkage in over 90% of trial participants; however, consent and participant withdrawals were common limitations to participant linkage. Reported advantages were the reliability and accuracy of the data, the ease of long term follow-up, and the use of established data linkage units. Common reported limitations were locating participants who had moved outside the jurisdictional area, missing data where consent was not provided, and unavailability of certain healthcare data. CONCLUSIONS: As linked administrative data are not intended for research purposes, detailed knowledge of the data sets is required by researchers, and the time delay in receiving the data is viewed as a barrier to its use. The lack of access to primary care data sets is viewed as a barrier to administrative data use; however, work to expand the number of healthcare data sets that can be linked has made it easier for researchers to access and use these data, which may have implications on how randomised controlled trials will be run in future.

Testosterone therapy to prevent type 2 diabetes mellitus in at-risk men (T4DM): Design and implementation of a double-blind randomized controlled trial.

BACKGROUND: Low circulating testosterone is associated with an increased risk of developing type 2 diabetes (T2DM) in overweight men with impaired glucose tolerance (IGT). AIMS: To determine in a multi-centre, double-blinded placebo-controlled randomized trial whether testosterone treatment combined with lifestyle intervention (Weight Watchers) relative to lifestyle intervention alone reduces T2DM incidence and improves glucose tolerance at 2 years. STUDY POPULATION: Overweight or obese men aged 50-74 years with a serum testosterone of ≤14 nmol/L and IGT or newly diagnosed T2DM established by an oral glucose tolerance test (OGTT). SETTING, DRUG AND PROTOCOL: Six Australian capital city-based tertiary care centres. Participants were randomized 1:1 and injected with testosterone undecanoate (1000 mg/4 mL) or vehicle (4 mL castor oil), at baseline, 6 weeks and 3-monthly thereafter. PRIMARY ENDPOINTS: (a) Proportion of participants with 2-hour OGTT ≥11.1 mmol/L at 2 years, and (b) a difference at 2 years ≥0.6 mmol/L in the mean 2-hour OGTT glucose between treatments. SECONDARY ENDPOINTS: Fasting insulin, HbA1c, body composition, maximal handgrip strength; sexual function and lower urinary tract symptoms; serum sex steroids and sex hormone binding globulin; mood and psychosocial function; adherence to lifestyle intervention; and healthcare utilization and costs. SAFETY: Overseen by an Independent Data Safety Monitoring Committee. Haematocrit, lipids and prostate-specific antigen (PSA) are assessed 6-monthly and information relating to haematological, urological and cardiovascular adverse events from each clinic visit. SUB-STUDIES: (a) Changes in bone density and micro-architecture, (b) motivation and behaviour, (c) telomere length, (d) extended treatment up to 4 years, and (e) hypothalamo-pituitary testicular axis recovery at treatment end.

A high-volume, low-cost approach to participant screening and enrolment: Experiences from the T4DM diabetes prevention trial.

BACKGROUND/AIMS: Participant recruitment to diabetes prevention randomised controlled trials is challenging and expensive. The T4DM study, a multicentre, Australia-based, Phase IIIb randomised controlled trial of testosterone to prevent Type 2 diabetes in men aged 50-74 years, faced the challenge of screening a large number of prospective participants at a small number of sites, with few staff, and a limited budget for screening activities. This article evaluates a high-volume, low-cost, semi-automated approach to screen and enrol T4DM study participants. METHODS: We developed a sequential multi-step screening process: (1) web-based pre-screening, (2) laboratory screening through a network of third-party pathology centres, and (3) final on-site screening, using online data collection, computer-driven eligibility checking, and automated, email-based communication with prospective participants. Phone- and mail-based data collection and communication options were available to participants at their request. The screening process was administered by the central coordinating centre through a central data management system. RESULTS: Screening activities required staffing of approximately 1.6 full-time equivalents over 4 years. Of 19,022 participants pre-screened, 13,108 attended a third-party pathology collection centre for laboratory screening, 1217 received final, on-site screening, and 1007 were randomised. In total, 95% of the participants opted for online pre-screening over phone-based pre-screening. Screening costs, including both direct and staffing costs, totalled AUD1,420,909 (AUD75 per subject screened and AUD1411 per randomised participant). CONCLUSION: A multi-step, semi-automated screening process with web-based pre-screening facilitated low-cost, high-volume participant enrolment to this large, multicentre randomised controlled trial. Centralisation and automation of screening activities resulted in substantial savings compared to previous, similar studies. Our screening approach could be adapted to other randomised controlled trial settings to minimise the cost of screening large numbers of participants.

Using the Behaviour Change Wheel to identify barriers and targeted strategies to improve adherence in randomised clinical trials: The example of MEL-SELF trial of patient-led surveillance for melanoma.

BACKGROUND: Adherence to self-management interventions is critical in both clinical settings and trials to ensure maximal effectiveness. This study reports how the Behaviour Change Wheel may be used to assess barriers to self-management behaviours and develop strategies to maximise adherence in a trial setting (the MEL-SELF trial of patient-led melanoma surveillance). METHODS: The Behaviour Change Wheel was applied by (i) using the Capability, Opportunity, Motivation-Behaviour (COMB) model informed by empirical and review data to identify adherence barriers, (ii) mapping identified barriers to corresponding intervention functions, and (iii) identifying appropriate behaviour change techniques and developing potential solutions using the APEASE (Affordability, Practicability, Effectiveness and cost-effectiveness, Acceptability, Side-effects and safety, Equity) criteria. RESULTS: The target adherence behaviour was defined as conducting a thorough skin self-examination and submitting images for teledermatology review. Key barriers identified included: non-engaged skin check partners, inadequate planning, time constraints, low self-efficacy, and technological difficulties. Participants' motivation was positively influenced by perceived health benefits and negatively impacted by emotional states such as anxiety and depression. We identified the following feasible interventions to support adherence: education, training, environmental restructuring, enablement, persuasion, and incentivisation. Proposed solutions included action planning, calendar scheduling, alternative dermatoscopes, optimised communication, educational resources in various formats to boost self-efficacy and motivation and optimised reminders (which will be evaluated in a Study Within A Trial (SWAT)). CONCLUSION: The Behaviour Change Wheel may be used to improve adherence in clinical trials by identifying barriers to self-management behaviours and guiding development of targeted strategies.

Testosterone Treatment, Weight Loss, and Health-related Quality of Life and Psychosocial Function in Men: A 2-year Randomized Controlled Trial.

OBJECTIVE: To determine the effect of testosterone vs placebo treatment on health-related quality of life (HR-QOL) and psychosocial function in men without pathologic hypogonadism in the context of a lifestyle intervention. DESIGN, SETTING, PARTICIPANTS: Secondary analysis of a 2-year randomized controlled testosterone therapy trial for prevention or reversal of newly diagnosed type 2 diabetes, enrolling men ≥ 50 years at high risk for type 2 diabetes from 6 Australian centers. INTERVENTIONS: Injectable testosterone undecanoate or matching placebo on the background of a community-based lifestyle program. MAIN OUTCOMES: Self-reported measures of HR-QOL/psychosocial function. RESULTS: Of 1007 participants randomized into the Testosterone for Type 2 Diabetes Mellitus (T4DM) trial, 648 (64%) had complete data available for all HR-QOL/psychosocial function assessments at baseline and 2 years. Over 24 months, while most measures were not different between treatment arms, testosterone treatment, compared with placebo, improved subjective social status and sense of coherence. Baseline HR-QOL/psychosocial function measures did not predict the effect of testosterone treatment on glycemic outcomes, primary endpoints of T4DM. Irrespective of treatment allocation, larger decreases in body weight were associated with improved mental quality of life, mastery, and subjective social status. Men with better baseline physical function, greater sense of coherence, and fewer depressive symptoms experienced greater associated decreases in body weight, with similar effects on waist circumference. CONCLUSION: In this diabetes prevention trial, weight loss induced by a lifestyle intervention improved HR-QOL and psychosocial function in more domains than testosterone treatment. The magnitude of weight and waist circumference reduction were predicted by baseline physical function, depressive symptomology, and sense of coherence.

Efficacy and safety of pentosan polysulfate sodium in people with symptomatic knee osteoarthritis and dyslipidaemia: protocol of the MaRVeL trial.

INTRODUCTION: Knee osteoarthritis (OA) is the most prevalent arthritis type and a leading cause of chronic mobility disability. While pain medications provide only symptomatic pain relief; growing evidence suggests pentosan polysulfate sodium (PPS) is chondroprotective and could have anti-inflammatory effects in knee OA. This study aims to explore the efficacy and safety of oral PPS in symptomatic knee OA with dyslipidaemia. METHODS AND ANALYSIS: MaRVeL is a phase II, single-centre, parallel, superiority trial which will be conducted at Royal North Shore Hospital, Sydney, Australia. 92 participants (46 per arm) aged 40 and over with painful knee OA and mild to moderate structural change on X-ray (Kellgren and Lawrence grade 2 or 3) will be recruited from the community and randomly allocated to receive two cycles of either oral PPS or placebo for 5 weeks starting at baseline and week 11. Primary outcome will be the 16-week change in overall average knee pain severity measured using an 11-point Numeric Rating Scale. Main secondary outcomes include change in knee pain, patient global assessment, physical function, quality of life and other structural changes. A biostatistician blinded to allocation groups will perform the statistical analysis according to the intention-to-treat principle. ETHICS AND DISSEMINATION: The protocol has been approved by the NSLHD Human Research Ethics Committee (HREC) (2021/ETH00315). All participants will provide written informed consent online. Study results will be disseminated through conferences, social media and academic publications. TRIAL REGISTRATION NUMBERS: Australian New Zealand Clinical Trial Registry (ACTRN12621000654853); U1111-1265-3750.

Efficacy and safety of an oral complementary medicine combination in people with symptomatic knee osteoarthritis: Protocol for the double-blind, randomized, placebo-controlled ATLAS trial.

Objective: To investigate the efficacy and safety of an oral complementary medicine combination formulation relative to placebo, on changes in pain intensity from baseline to week 12, in people with knee osteoarthritis (OA). Design: A placebo-controlled, double-blind, two-arm, superiority, phase II, Randomized Controlled Trial (RCT) (ACTRN12623000380695). We will recruit 82 participants (∼41 per arm), aged ≥40 years, with a clinical diagnosis of symptomatic knee OA and radiographic change on x-ray (Kellgren-Lawrence Grade ≥2). Participants will be randomly allocated to receive either a complementary medicine formulation containing a daily dose of Boswellia serrata extract (Boswellin® Super, 250 â€‹mg/day), pine bark extract (Fenoprolic™ 70 Organic 100 â€‹mg/day), curcumin (500 â€‹mg/day), piperine (5 â€‹mg/day), and methylsulfonylmethane (MSM, 1500 â€‹mg/day), or placebo, for 12-weeks. The primary endpoint will be change from baseline in average knee pain intensity at 12-weeks (visual analogue scale). Secondary endpoints will include change in knee pain from baseline to 12-weeks in the Knee Injury and Osteoarthritis Outcome Score (KOOS), global assessment of disease activity, global rating of change, and health-related quality of life (AQoL-8D). Ethics and dissemination: This protocol has been approved by the University of Sydney Human Research Ethics Committee (#2021/877). Dissemination will occur through lay summaries, infographics, conference abstracts, oral presentations, theses, and scientific publications. Conclusion: This RCT will provide credible evidence about the efficacy and safety of this complementary medicine combination and inform updates to international clinical practice standards on the use of complementary medicines in the management of symptomatic knee OA.

The importance of NOT being Other: Time to address the invisibility of nuanced gender and sexuality in clinical trials.

BACKGROUND: Representation of all members of society within research, especially those typically underserved, is needed to ensure that trial evidence applies to the relevant population, and that effective interventions are available to all. The lack of appropriate and representative options in demographic questions around sex, gender and sexuality may result in the exclusion of LGBTQIA + people from health research. MAIN BODY: Sex and gender are not the same, yet this is rarely recognised in trial data collection, with the terms sex and gender often being used interchangeably. Sex or gender is often used as a stratification factor at randomisation and/or to define sub-groups at the time of data analysis, so correct data collection is essential for producing high-quality science. Sexuality also suffers from 'othering' with identities not being acknowledged but simply provided as an alternative to the perceived main identities. When collecting sexuality information, it is important to consider the purposes of collecting this data. CONCLUSION: We call on those involved in trials to consider how sex, gender and sexuality data are collected, with an active consideration of inclusivity. Through the description of all non-straight, non-cisgender people as 'other' you may be ignoring the needs of these populations and doing science, yourself, and them a disservice. Inclusivity may require small but important changes to ensure your research findings are inclusive and develop the evidence base for often overlooked populations.

Strategies to Improve Adherence to Skin Self-examination and Other Self-management Practices in People at High Risk of Melanoma: A Scoping Review of Randomized Clinical Trials.

Importance: Adherence, both in research trials and in clinical practice, is crucial to the success of interventions. There is limited guidance on strategies to increase adherence and the measurement and reporting of adherence in trials of melanoma self-management practices. Objective: This scoping review aimed to describe (1) strategies to improve adherence to self-management practices in randomized clinical trials of people at high risk of melanoma and (2) measurement and reporting of adherence data in these trials. Evidence Review: Four databases, including MEDLINE, Embase, CENTRAL, and CINAHL, were searched from inception to July 2022. Eligible studies were randomized clinical trials of self-monitoring interventions for early detection of melanoma in people at increased risk due to personal history (eg, melanoma, transplant, dysplastic naevus syndrome), family history of melanoma, or as determined by a risk assessment tool or clinical judgment. Findings: From 939 records screened, 18 eligible randomized clinical trials were identified, ranging in size from 40 to 724 participants, using a range of adherence strategies but with sparse evidence on effectiveness of the strategies. Strategies were classified as trial design (n = 15); social and economic support (n = 5); intervention design (n = 18); intervention and condition support (n = 10); and participant support (n = 18). No strategies were reported for supporting underserved groups (eg, people who are socioeconomically disadvantaged, have low health literacy, non-English speakers, or older adults) to adhere to self-monitoring practices, and few trials targeted provider (referring to both clinicians and researchers) adherence (n = 5). Behavioral support tools included reminders (n = 8), priority-setting guidance (n = 5), and clinician feedback (n = 5). Measurement of adherence was usually by participant report of skin self-examination practice with some recent trials of digital interventions also directly measuring adherence to the intervention through website or application analytic data. Reporting of adherence data was limited, and fewer than half of all reports mentioned adherence in their discussion. Conclusions and Relevance: Using an adaptation of the World Health Organization framework for clinical adherence, this scoping review of randomized clinical trials identified key concepts as well as gaps in the way adherence is approached in design, conduct, and reporting of trials for skin self-examination and other self-management practices in people at high risk of melanoma. These findings may usefully guide future trials and clinical practice; evaluation of adherence strategies may be possible using a Study Within A Trial (SWAT) framework within host trials.

Long-term Outcomes of Testosterone Treatment in Men: A T4DM Postrandomization Observational Follow-up Study.

CONTEXT: The T4DM study randomized 1007 men with impaired glucose tolerance or newly diagnosed diabetes to testosterone undecanoate (TU, 1000 mg) or matching placebo (P) injections every 12 weeks for 24 months with a lifestyle program with testosterone (T) treatment reducing diabetes diagnosis by 40%. BACKGROUND: The long-term effects on new diagnosis of diabetes, cardiovascular and prostate disease, sleep apnea, weight maintenance trajectory and androgen dependence were not yet described. METHODS: A follow-up email survey after a median of 5.1 years since last injection obtained 599 (59%) completed surveys (316 T, 283 P), with participants in the follow-up survey compared with nonparticipants in 23 anthropometric and demographic variables. RESULTS: Randomization to was TU associated with stronger belief in study benefits during (64% vs 49%, P < .001) but not after the study (44% vs 40%, P = .07); there is high interest in future studies. At T4DM entry, 25% had sleep apnea with a new diagnosis more frequent on TU (3.0% vs 0.4%, P = .03) during, but not after, the study. Poststudy, resuming prescribed T treatment was more frequent among TU-treated men (6% vs 2.8%, P = .03). Five years after cessation of TU treatment there was no difference in self-reported rates of new diagnosis of diabetes, and prostate or cardiovascular disease, nor change in weight maintenance or weight loss behaviors. CONCLUSION: We conclude that randomized T treatment for 24 months in men with impaired glucose tolerance or new diabetes but without pathological hypogonadism was associated with higher levels of self-reported benefits and diagnosis of sleep apnea during, but not after, the study as well as more frequent prescribed poststudy T treatment consistent with androgen dependence in some men receiving prolonged injectable TU.