RCT Participants Research Articles

The response of Canada's clinical health research ecosystem to the COVID-19 pandemic.

The response of Canada's research community to the COVID-19 pandemic provides a unique opportunity to examine the country's clinical health research ecosystem. We sought to describe patterns of enrolment across Canadian Institutes of Health Research (CIHR)-funded studies on COVID-19. We identified COVID-19 studies funded by the CIHR and that enrolled participants from Canadian acute care hospitals between January 2020 and April 2023. We collected information on study-and site-level variables from study leads, site investigators, and public domain sources. We described and evaluated factors associated with cumulative enrolment. We obtained information for 23 out of 26 (88%) eligible CIHR-funded studies (16 randomized controlled trials [RCTs] and 7 cohort studies). The 23 studies were managed by 12 Canadian and 3 international coordinating centres. Of 419 Canadian hospitals, 97 (23%) enrolled a total of 28 973 participants - 3876 in RCTs across 78 hospitals (median cumulative enrolment per hospital 30, interquartile range [IQR] 10-61), and 25 097 in cohort studies across 62 hospitals (median cumulative enrolment per hospital 158, IQR 6-348). Of 78 hospitals recruiting participants in RCTs, 13 (17%) enrolled 50% of all RCT participants, whereas 6 of 62 hospitals (9.7%) recruited 54% of participants in cohort studies. A minority of Canadian hospitals enrolled the majority of participants in CIHR-funded studies on COVID-19. This analysis sheds light on the Canadian health research ecosystem and provides information for multiple key partners to consider ways to realize the full research potential of Canada's health systems.

The influence of bias in randomized controlled trials on rehabilitation intervention effect estimates: what we have learned from meta-epidemiological studies.

This study aimed to synthesize evidence from studies that addressed the influence of bias domains in randomized controlled trials on rehabilitation intervention effect estimates and discuss how these findings can maximize the trustworthiness of an RCT in rehabilitation. We screened studies about the influence of bias on rehabilitation intervention effect estimates published until June 2023. The characteristics and results of the included studies were categorized based on methodological characteristics and summarized narratively. We included seven studies with data on 227,806 RCT participants. Our findings showed that rehabilitation intervention effect estimates are likely exaggerated in trials with inadequate/unclear sequence generation and allocation concealment when using continuous outcomes. The influence of blinding was inconsistent and different from the rest of medical science, as meta-epidemiological studies showed overestimation, underestimation, or neutral associations for different types of blinding on rehabilitation treatment effect estimates. Still, it showed a more consistent pattern when looking at patient-reported outcomes. The impact of attrition bias and intention to treat has been analyzed only in two studies with inconsistent results. The risk of reporting bias seems to be associated with overestimation of treatment effects. Bias domains can influence rehabilitation treatment effects in different directions. The evidence is mixed and inconclusive due to the poor methodological quality of RCTs and the limited number and quality of studies looking at the influence of bias and treatment effects in rehabilitation. Further studies about the influence of bias in RCTs on rehabilitation intervention effect estimates are needed.

Abstract 12401: Multidimensional Representativeness of Older Adults With Atrial Fibrillation in Randomized Controlled Trials: Comparing Participants of 12 Oral Anticoagulant RCTs to a Nationally Representative US Cohort

Background: Anticoagulant RCTs are thought to have enrolled younger and less comorbid patients with atrial fibrillation (AF) compared to the general population. We developed a representation score summarizing patient characteristics to describe how well RCT participants with AF reflect a nationally representative cohort. Methods: We studied adults >=65 years old with AF by harmonizing two data sources: (1) patient-level data from 12 landmark RCTs testing anticoagulants vs. placebo or antiplatelets from the Atrial Fibrillation Investigators (AFI) consortium and (2) the Health and Retirement Study AF cohort (HRS-AF), a representative cohort of older adults with AF in the U.S. We fit a logistic regression model to estimate the probability of inclusion in the HRS-AF cohort in the pooled sample using age, height, weight, gender, heart failure, hypertension, diabetes, prior stroke, and prior myocardial infarction. This estimate, the Trial Benchmark Score, reflected the probability of belonging to the HRS-AF cohort and ranged from 0 to 1, with higher scores reflecting a greater likelihood of belonging to the HRS-AF cohort. We plotted the distribution of scores for HRS-AF and AFI participants and compared the mean scores using a t-test. Results: Compared to the HRS-AF cohort (n=3542), AFI participants (n=7933) were younger (72 vs. 76yrs, standardized mean difference [SMD] -0.7), more frequently male (64% vs. 46%, SMD 0.3), and had a lower likelihood of prior stroke (19% vs. 23%, SMD -0.4). The mean Trial Benchmark Score differed significantly between the two cohorts (HRS-AF mean 0.47 vs. AFI mean 0.23, p<0.001) ( Figure ). 52% of HRS-AF participants and 12% of AFI participants had a score >0.47 (the HRS-AF mean score). Conclusion: Differences in the Trial Benchmark Scores distributions indicate a substantial difference in the distribution of observable characteristics and that RCT participants were not fully representative of the benchmark population.

Causal relationships between pain, medical treatments, and knee osteoarthritis: A graphical causal model to guide analyses

ObjectiveRandomized controlled trials (RCTs) are a gold standard for estimating the benefits of clinical interventions, but their decision-making utility can be limited by relatively short follow-up time. Longer-term follow-up of RCT participants is essential to support treatment decisions. However, as time from randomization accrues, loss to follow-up and competing events can introduce biases and require covariate adjustment even for intention-to-treat effects. We describe a process for synthesizing expert knowledge and apply this to long-term follow-up of an RCT of treatments for meniscal tears in patients with knee osteoarthritis (OA). MethodsWe identified 2 post-randomization events likely to impact accurate assessment of pain outcomes beyond 5 years in trial participants: loss to follow-up and total knee replacement (TKR). We conducted literature searches for covariates related to pain and TKR in individuals with knee OA and combined these with expert input. We synthesized the evidence into graphical models. ResultsWe identified 94 potential covariates potentially related to pain and/or TKR among individuals with knee OA. Of these, 46 were identified in the literature review and 48 by expert panelists. We determined that adjustment for 50 covariates may be required to estimate the long-term effects of knee OA treatments on pain. ConclusionWe present a process for combining literature reviews with expert input to synthesize existing knowledge and improve covariate selection. We apply this process to the long-term follow-up of a randomized trial and show that expert input provides additional information not obtainable from literature reviews alone.

Precise unbiased estimation in randomized experiments using auxiliary observational data

Abstract Randomized controlled trials (RCTs) admit unconfounded design-based inference – randomization largely justifies the assumptions underlying statistical effect estimates – but often have limited sample sizes. However, researchers may have access to big observational data on covariates and outcomes from RCT nonparticipants. For example, data from A/B tests conducted within an educational technology platform exist alongside historical observational data drawn from student logs. We outline a design-based approach to using such observational data for variance reduction in RCTs. First, we use the observational data to train a machine learning algorithm predicting potential outcomes using covariates and then use that algorithm to generate predictions for RCT participants. Then, we use those predictions, perhaps alongside other covariates, to adjust causal effect estimates with a flexible, design-based covariate-adjustment routine. In this way, there is no danger of biases from the observational data leaking into the experimental estimates, which are guaranteed to be exactly unbiased regardless of whether the machine learning models are “correct” in any sense or whether the observational samples closely resemble RCT samples. We demonstrate the method in analyzing 33 randomized A/B tests and show that it decreases standard errors relative to other estimators, sometimes substantially.

Identifying eating disorders in adolescents and adults with overweight or obesity: A systematic review of screening questionnaires.

ObjectiveThis review aimed to examine the validity of self‐report screening questionnaires for identifying eating disorder (ED) risk in adults and adolescents with overweight/obesity.MethodFive databases were searched from inception to September 2020 for studies assessing validation of self‐report ED screening questionnaires against diagnostic interviews in adolescents and adults with overweight/obesity. The review was registered with PROSPERO (https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=220013).ResultsTwenty‐seven papers examining 15 questionnaires were included. Most studies validated questionnaires for adults (22 of 27 studies), and most questionnaires (12 of 15) screened for binge eating or binge‐eating disorder (BED). The Eating Disorder Examination Questionnaire (sensitivity = .16–.88, specificity = .62–1.0) and Questionnaire on Eating and Weight Patterns (sensitivity = .07–1.0, specificity = .0–1.0) were most frequently validated (six studies each). Five studies of three questionnaires were in adolescents, with the Adolescent Binge‐Eating Disorder Questionnaire having highest sensitivity (1.0) but lower specificity (.27). Questionnaires designed to screen for BED generally had higher diagnostic accuracy than those screening for EDs in general.DiscussionQuestionnaires have been well validated to identify BED in adults with overweight/obesity. Validated screening tools to identify other EDs in adults and any ED in adolescents with overweight/obesity are lacking. Thus, clinical assessment should inform the identification of patients with co‐morbid EDs and overweight/obesity.Public SignificanceIndividuals with overweight/obesity are at increased risk of EDs. This review highlights literature gaps regarding screening for ED risk in this vulnerable group. This work presents possibilities for improving care of individuals with overweight/obesity by reinventing ED screening tools to be better suited to diverse populations.

Emulating the MERINO randomised control trial using data from an observational cohort and trial of rapid diagnostic (BSI-FOO).

ObjectiveThe aim of this study was to emulate the MERINO trial of piperacillin-tazobactam vs meropenem for the definitive treatment of bloodstream infection (BSI) caused by ceftriaxone-nonsusceptible E coli or Klebsiella spp.MethodsData from an observational study of BSI and a randomised controlled trial of a rapid diagnostic in BSI were used to emulate the MERINO trial. The primary outcome of the emulated trial was 28-day mortality after blood culture. Outcomes were compared using logistic regression adjusted for propensity score for emulated intervention.ResultsOf the 6,371 observational study and RCT participants, 1,968 had a bloodstream infection with E. coli or Klebsiella spp. of which 121 met the eligibility criteria. In the emulated trial, a total of 14/82 patients (17.1%) allocated to piperacillin-tazobactam met the primary outcome compared with 6/39 (15.4%) in the meropenem group (unadjusted odds ratio 1.13 (95% CI 0.40 to 3.21)). After adjustment for propensity score, the odds ratio increased to 1.31 (95% CI 0.40 to 4.26). This difference is in the same direction but of a smaller magnitudethan observed in the MERINO trial, where 30-day mortality was met by 23/187 patients (12.3%) in the piperacillin-tazobactam and 7/191 (3.7%) in the meropenem group (unadjusted odds ratio of 3.69 (95% CI 1.48 to 10.41)).ConclusionsThe mortality rate in an emulated trial population was more than double the mortality rate in the MERINO trial. The methodology used attempts to address the concern that previous results could be explained by biases such as selection bias and uncontrolled confounding and provides information on how a trial such as the MERINO trial may have performed in the NHS.

Cardiometabolic health risks, lifestyle behaviours and quality of life in people diagnosed with early psychosis – A cross‐sectional study

WHAT IS KNOWN ON THE SUBJECT?: People diagnosed with schizophrenia have poor cardiometabolic health, with elevated 10-year cardiovascular disease risk (CVD-R) scores and low quality of life (QOL). There is a lack of understanding about CVD-R scores in people diagnosed with early psychosis and no studies have quantified CVD-R using the QRISK® 3calculator in this client group. Establishing potential relationships between modifiable lifestyle behaviours/treatment characteristics with CVD-R or QOL may identify targets for early intervention. WHAT THE PAPER ADDS TO EXISTING KNOWLEDGE?: This is the first study to quantify the individual 10-year CVD-R of people diagnosed with early psychosis utilising the QRISK® 3calculator. This is also the first study to investigate relationships between QOL and CVD-R and lifestyle factors in a cohort of Thai people diagnosed with early psychosis. We observed low levels of physical health-related QOL and high levels of CVR-R despite participants reporting relatively positive lifestyle behaviours. WHAT ARE THE IMPLICATIONS FOR PRACTICE?: The cardiometabolic health state of this client group warrants as much attention as for those with an enduring severe mental illness; early preventative interventions are warranted. It may be useful to routinely quantify the CVD-R of people diagnosed with early psychosis using the QRISK® 3calculator, even in the absence of immediate concerns about lifestyle behaviours. Mental health nurses should utilise evidence-based approaches such as increasing activity levels, dietary counselling and behaviour change interventions to mitigate poor physical health in this client group. ABSTRACT: Introduction People diagnosed with schizophrenia have poor cardiometabolic health, with elevated 10-year cardiovascular disease risk (CVD-R) scores and poor quality of life (QOL). There is lack of understanding of these issues in early psychosis. Aims To quantify CVD-R in people diagnosed with early psychosis and profile their obesity prevalence, lifestyle behaviours and QOL. Secondary aim was to explore associations between lifestyle behaviours/treatment characteristics and CVD-R/QOL. Method Baseline data from 81 RCT participants were used to profile cardiometabolic health risks (QRISK® 3, BMI and waist circumference). Participants self-reported lifestyle behaviours and QOL. Relationships between modifiable treatment/lifestyle factors and QOL/CVD-R were explored. Results Participants' relative risk for CVD over 10years was 1.93 times higher than healthy counterparts; 39% also had an obese BMI and physical QOL was poor. No significant associations were observed between CVD-R or QOL with treatment characteristics and lifestyle factors. Discussion Despite positive lifestyle behaviours, participants had elevated CVD-R scores and poor physical health-related QOL. Quantifying CVD-R with QRISK® 3may highlight the need for health promotion interventions. Implications for practice Mental health professionals should be aware that elevated CVD-R exists in the context of relatively healthy lifestyle behaviours and utilise evidence-based interventions to address these issues.

Continuous positive airway pressure and adverse cardiovascular events in obstructive sleep apnea: are participants of randomized trials representative of sleep clinic patients?

Randomized controlled trials (RCTs) have shown no reduction in adverse cardiovascular (CV) events in patients randomized to continuous positive airway pressure (CPAP) therapy for obstructive sleep apnea (OSA). This study examined whether randomized study populations were representative of OSA patients attending a sleep clinic. Sleep clinic patients were 3,965 consecutive adults diagnosed with OSA by in-laboratory polysomnography from 2006 to 2010 at a tertiary hospital sleep clinic. Characteristics of these patients were compared with participants of five recent RCTs examining the effect of CPAP on adverse CV events in OSA. The percentage of patients with severe (apnea-hypopnea index, [AHI] ≥ 30 events/h) or any OSA (AHI ≥ 5 events/h) who met the eligibility criteria of each RCT was determined, and those criteria that excluded the most patients identified. Compared to RCT participants, sleep clinic OSA patients were younger, sleepier, more likely to be female and less likely to have established CV disease. The percentage of patients with severe or any OSA who met the RCT eligibility criteria ranged from 1.2% to 20.9% and 0.8% to 21.9%, respectively. The eligibility criteria that excluded most patients were preexisting CV disease, symptoms of excessive sleepiness, nocturnal hypoxemia and co-morbidities. A minority of sleep clinic patients diagnosed with OSA meet the eligibility criteria of RCTs of CPAP on adverse CV events in OSA. OSA populations in these RCTs differ considerably from typical sleep clinic OSA patients. This suggests that the findings of such OSA treatment-related RCTs are not generalizable to sleep clinic OSA patients.Randomized Intervention with Continuous Positive Airway Pressure in CAD and OSA (RICCADSA) trial, https://clinicaltrials.gov/ct2/show/NCT00519597, ClinicalTrials.gov number, NCT00519597.Usefulness of Nasal Continuous Positive Airway Pressure (CPAP) Treatment in Patients with a First Ever Stroke and Sleep Apnea Syndrome, https://clinicaltrials.gov/ct2/show/NCT00202501, ClinicalTrials.gov number, NCT00202501.Effect of Continuous Positive Airway Pressure (CPAP) on Hypertension and Cardiovascular Morbidity-Mortality in Patients with Sleep Apnea and no Daytime Sleepiness, https://clinicaltrials.gov/ct2/show/NCT00127348, ClinicalTrials.gov number, NCT00127348.Continuous Positive Airway Pressure (CPAP) in Patients with Acute Coronary Syndrome and Obstructive Sleep Apnea (OSA) (ISAACC), https://clinicaltrials.gov/ct2/show/NCT01335087, ClinicalTrials.gov number, NCT01335087.

P119 CPAP and adverse cardiovascular events in OSA: Are participants of randomized trials representative of sleep clinic patients?

Abstract Introduction Randomized controlled trials (RCTs) have shown no reduction in adverse cardiovascular (CV) events in patients randomized to continuous positive airway pressure (CPAP) therapy for obstructive sleep apnea (OSA). This study examined whether randomized study populations were representative of OSA patients attending a sleep clinic. Methods Sleep clinic patients were 3,965 consecutive adults diagnosed with OSA by in-laboratory polysomnography from 2006–2010 at a tertiary hospital sleep clinic. Characteristics of these sleep clinic OSA patients were compared with participants of 5 well-known RCTs examining the effect of CPAP on adverse CV events in OSA. We determined the percentage of patients with severe (apnea hypopnea index, [AHI]≥30/h) or any OSA (AHI≥5/h) who met the selection criteria of each RCT, as well as identified those criteria that excluded the most patients. Results Compared to RCT participants, sleep clinic OSA patients were younger, sleepier, more likely to be female and less likely to have established CV disease. The percentage of patients with severe or any OSA who met the RCT selection criteria ranged from 1.2% to 20.2% and 0.8% to 21.1%, respectively. The selection criteria that excluded most patients were pre-existing CV disease, symptoms of excessive sleepiness, nocturnal hypoxemia and co-morbidities. Discussion A minority of sleep clinic patients diagnosed with OSA meet the selection criteria of RCTs of CPAP on adverse CV events in OSA. OSA populations in RCTs differ considerably from typical sleep clinic OSA patients. This suggests that the findings of RCTs may not be generalisable to most sleep clinic OSA patients.

Development and validation of an EHR data-based program to identify eligible RCT participants.

338 Background: Identifying participants for time-sensitive clinical trials such as those with newly diagnosed cancer presents challenges. Manual identification methods, the current standard, can be resource intensive and present challenges with data collection, quality assurance and can introduce bias to the selection process. Electronic health record (EHR) data, designed to optimize clinical care, quality, and billing, may also streamline participant identification and facilitate recruitment. We aim to develop an EHR-based study eligibility program (SEP) to identify participants for recruitment to the Cancer Financial Experience (CAFÉ) randomized trial. Methods: CAFÉ is a NIH-funded randomized trial to test the impact of a novel financial navigation intervention on financial hardship and quality of life for cancer patients. Inclusion criteria: currently enrolled at Kaiser Permanente (KP) Northwest or KP Washington, age ≥18, had a visit to a CAFÉ-participating oncology clinic within last 14 days (defined as qualifying visit), diagnosed with invasive cancer (new or recurrent) within 120 days of qualifying visit, 6 months continuous enrollment prior to qualifying visit, English or Spanish speaker. Exclusion criteria: diagnosis of non-melanoma skin cancer, diagnosis of benign or in-situ tumors, hospice care within last 12 months, unable to complete baseline survey, household member enrolled in CAFÉ study. To assess the validity of the SEP for use in CAFÉ, we extracted EHR data on study inclusion/exclusion criteria for n = 125 patients across both study sites between 3/1/19–2/29/20 to determine eligibility status (eligible, ineligible). Manual EHR review was then conducted on the n = 125 patients to assess inclusion/exclusion criteria and determine eligibility. Results of SEP vs. manual review were compared, noting reasons for discrepancies. Positive predictive value (PPV), negative predictive value (NPV), sensitivity and specificity values were calculated. We herein report results of one site (n = 75), with next steps to complete analysis of the total n = 125 at both sites. Results: The SEP had a PPV of 76%, NPV of 96%, sensitivity of 97% and specificity of 67%, based on n = 75 patients. We identified areas of improvement for the SEP and groups to conduct manual validation during the CAFÉ trial. Potential reasons for lower specificity and lower PPV include: the SEP was identifying patients with a hematologic malignancy (e.g., lymphoma) and a recent visit to oncology, but whose diagnosis date was outside the eligible period; additionally, the SEP was identifying patients with a recent oncology visit, but who had a non-cancer diagnosis (e.g., monoclonal gammopathy of undetermined significance [MGUS]). Conclusions: Development of a validated EHR-based tool to rapidly identify cancer clinical trial participants offers a low resource option that may overcome challenges associated with manual chart review.

Urban RCT participants were healthier than non-participants or rural women

ObjectiveTo investigate sociodemographic characteristics and physical and mental health indicators between participants and nonparticipants of a large-scale 2-year exercise RCT including noninvited women living in nearby rural area in Finland. Study Design and SettingFrom a previous OSTPRE study cohort, 914 women (aged 72–84) participated in Kuopio Fall Prevention Study in 2016–2019. The participants were compared to non-participants (n = 4,536) and noninvited OSTPRE women (n = 7,119) living outside the urban recruitment area. ResultsParticipants were younger (P< 0.001) with higher education (P< 0.001) and had more often regular hobbies (P< 0.001) and physical exercising (P< 0.001) than nonparticipants or noninvited. They reported better functional capability (P< 0.001), mental (P< 0.001) and subjective health (P< 0.001), lower number of medications (P< 0.001), less fear of falls (P< 0.001), but more frequent falls (P= 0.002) and more often musculoskeletal diseases (P= 0.006). Participants also showed better functional capacity in the clinical measurements. In register analysis, urban-rural differences in the prevalence of diseases were detected. ConclusionIn population-based exercise interventions, participants are more likely to be better off in respect to physical and mental wellbeing, functional capability and sociodemographic status. Recruiting participants only from cities increases unavoidable selection bias due to urban-rural differences which should be noticed when interpreting and generalizing RCT results. Trial registration numberClinicalTrials.gov identifier NCT02665169.

Swallowing Exercise During Head and Neck Cancer Treatment: Results of a Randomized Trial

The diagnosis and treatment of head and neck cancer (HNC) can have substantial impact on swallowing function, nutritional balance, physical function and quality of life (QoL). Early initiated swallowing exercises are hypothesized to improve swallowing function in HNC patients. The aim was to investigate the effects of swallowing exercises and progressive resistance training (PRT) during radiotherapy on swallowing function, physical function and QoL in patients with pharynx-, larynx-, oral cavity cancer or unknown primary compared to usual care. In a multi-centre RCT participants were assigned to (a) twice-weekly PRT and daily swallowing exercises throughout treatment or (b) usual care. Outcomes were measured at end of treatment and 2, 6 and 12 months after. Primary outcome was penetration aspiration score (PAS). Data were analysed on an “intention-to-treat” basis by GEE logistic regression model, linear mixed effects model and cox regression. Of 371 invited HNC patients, 240 (65%) enrolled. Five participants were excluded. At 12 months follow-up, 59 (25%) participants were lost. Analyses showed significant effect on mouth opening, QoL, depression and anxiety at 12 months when comparing intervention to non-active controls. The trial found no effect on swallowing safety in HNC undergoing radiotherapy, but several positive effects were found on secondary outcomes when comparing to non-active controls. The intervention period may have been too short, and the real difference between groups is too small. Nevertheless, the need to identify long-lasting intervention to slow down or avoid functional deteriorations is ever more crucial as the surviving HNC population is growing.

POS0182 MINIMAL CLINICALLY IMPORTANT IMPROVEMENT (MCII) AND PATIENT ACCEPTABLE SYMPTOM STATE (PASS) FOR PAIN AND FUNCTION INSTRUMENTS IN HAND OSTEOARTHRITIS (OA)

Background:Australian/Canadian Hand OA Index (AUSCAN), Michigan Hand Outcomes Questionnaire (MHQ), Functional Index of Hand OA (FIHOA) and visual analogue scale (VAS) are frequently used instruments to measure pain and function in hand OA research. MCII and PASS are useful to interpret results of patient reported outcomes.Objectives:To estimate MCII and PASS for these instruments using anchor-based methods.Methods:Hand OA patients participating in a six-week randomised placebo-controlled trial with prednisolone (RCT; NTR5263) and those attending the two-year follow-up visit of the observational Hand OSTeoArthritiS cohort completed AUSCAN subscales pain and function, MHQ subscales pain, activities of daily living (ADL) and overall function, FIHOA and 100mm VAS pain. RCT participants were asked to indicate whether they changed compared to baseline (improved/no change/worse) and to rate the importance of improvement (very much/moderately/slightly/not at all). MCII was defined as the minimal improvement in symptoms achieved by 75% of participants who stated a slight/moderate improvement during the RCT, calculated as the 75th percentile of the distribution of change scores from baseline in this group. Absolute and relative percentage change were evaluated. For MCII direction of effect was unified, so positive values indicate worse symptoms and vice versa. Participants from both studies rated satisfaction with their state of health (acceptable/unacceptable). PASS was defined as the minimal score considered acceptable for 75% of participants, calculated as the 75th percentile of the distribution of scores in participants who rated their health ‘acceptable’.Results:Demographics of the RCT (n=92, mean age 63.9, 79% women) and cohort (n=383, 60.9 years, 84% women) participants were typical for hand OA. RCT participants were more symptomatic (e.g. mean [SD] VAS pain 54.0 [20.5] versus 35.2 [19.1]). Of the function instruments, only AUSCAN had a credible MCII (relative percentage improvement 9.8%), while the (positive) MCII values for FIHOA and MHQ subscales would indicate that worsening was rated as functional improvement (table 1). MCII was negative (corresponding to improvement) for all pain instruments, with relative percentage change around 25% for VAS and MHQ, compared to only 2% for AUSCAN. PASS values of all instruments were comparable in the two populations. Most instruments had a PASS around 50% of the possible maximum score, except for MHQ ADL, in which higher is better and a relatively high PASS is thus indicative of a floor effect (table 1).Conclusion:The only function instrument with an acceptable threshold for MCII was AUSCAN function, while for pain MHQ and VAS performed better than AUSCAN. PASS values show a relatively high level of tolerance of 50% of the maximum of the scale.Table 1.MCII and PASS of pain and function instruments in hand OA patients in two settings.MCII (95% CI) in RCT†PASS (95% CI)InstrumentAbsolute unitsPercentage[n]RCT (n=68)Cohort (n=126)MHQ Overall function, 0-100*3.4 (-2.7;9.5)3.6 (-9.1;16.3)[23]55.6 (52.6;58.5)48.1 (45.7;50.4) ADL, 0-100*1.6 (-4.4;7.6)2.8 (-9.6;15.3)[23]71.7 (68.2;75.1)62.9 (59.8;66.0) Pain, 0-100-12.2 (-17.2;-7.1)-23.1 (-35.4;-10.8)[16]47.0 (40.5;53.5)55.7 (52.0;59.5)AUSCAN Function, 0-36-3.3 (-5.7;-0.9)-9.8 (-23.9;4.2)[23]17.1 (15.3;19.0)20.9 (19.4;22.3) Pain, 0-20-1.1 (-2.6;0.4)-1.8 (-18.5;14.9)[27]9.0 (8.2;9.9)11.1 (10.3;11.8)FIHOA, 0-300.1 (-1.6;1.7)22.7 (-0.7;46.0)[23]12.4 (11.1;13.7)13.9 (12.8;15.0)VAS pain, 0-100-11.5 (-18.2;-4.7)-24.4 (-36.1;-12.8)[27]47.7 (42.2;53.3)48.8 (44.6;53.0)Direction of effect of all instruments is higher is worse, except those with *.†For all MCII direction of effect was unified, so positive values indicate worse symptoms and negative values values indicate improved symptoms.Disclosure of Interests:Féline Kroon: None declared, Lotte van de Stadt Grant/research support from: The HOSTAS and HOPE studies were sponsored by the Dutch Arthritis Society., Désirée van der Heijde: None declared, Margreet Kloppenburg Grant/research support from: The HOSTAS and HOPE studies were sponsored by the Dutch Arthritis Society.

E-Mental Health Program Usage Patterns in Randomized Controlled Trials and in the General Public to Inform External Validity Considerations: Sample Groupings Using Cluster Analyses.

BackgroundRandomized controlled trials (RCTs) with vigorous study designs are vital for determining the efficacy of treatments. Despite the high internal validity attributed to RCTs, external validity concerns limit the generalizability of results to the general population. Bias can be introduced, for example, when study participants who self-select into a trial are more motivated to comply with study conditions than are other individuals. These external validity considerations extend to e-mental health (eMH) research, especially when eMH tools are designed for public access and provide minimal or no supervision.ObjectiveClustering techniques were employed to identify engagement profiles of RCT participants and community users of a self-guided eMH program. This exploratory approach inspected actual, not theorized, RCT participant and community user engagement patterns. Both samples had access to the eMH program over the same time period and received identical usage recommendations on the eMH program website. The aim of this study is to help gauge expectations of similarities and differences in usage behaviors of an eMH tool across evaluation and naturalistic contexts.MethodsAustralian adults signed up to myCompass, a self-guided online treatment program created to reduce mild to moderate symptoms of negative emotions. They did so either by being part of an RCT onboarding (160/231, 69.6% female) or by accessing the program freely on the internet (5563/8391, 66.30% female) between October 2011 and October 2012. During registration, RCT participants and community users provided basic demographic information. Usage metrics (number of logins, trackings, and learning activities) were recorded by the system.ResultsSamples at sign-up differed significantly in age (P=.003), with community users being on average 3 years older (mean 41.78, SD 13.64) than RCT participants (mean 38.79, SD 10.73). Furthermore, frequency of program use was higher for RCT participants on all usage metrics compared to community users through the first 49 days after registration (all P values <.001). Two-step cluster analyses revealed 3 user groups in the RCT sample (Nonstarters, 10-Timers, and 30+-Timers) and 2 user groups in the community samples (2-Timers and 20-Timers). Groups seemed comparable in patterns of use but differed in magnitude, with RCT participant usage groups showing more frequent engagement than community usage groups. Only the high-usage group among RCT participants approached myCompass usage recommendations.ConclusionsFindings suggested that external validity concerns of RCT designs may arise with regards to the predicted magnitude of eMH program use rather than overall usage styles. Following up RCT nonstarters may help provide unique insights into why individuals choose not to engage with an eMH program despite generally being willing to participate in an eMH evaluation study. Overestimating frequency of engagement with eMH tools may have theoretical implications and potentially impact economic considerations for plans to disseminate these tools to the general public.

Consumer acceptability and validity of m-Health for the detection of adverse events following immunization – The Stimulated Telephone Assisted Rapid Safety Surveillance (STARSS) randomised control trial

IntroductionMonitoring for adverse events following immunisation (AEFI) is critical for vaccine pharmacovigilance. Given the global and expanding availability of mobile phones their utility for consumer-based vaccine safety surveillance is of interest but little is known about consumer acceptability. This study nested within the Stimulated Telephone Assisted Rapid Safety Surveillance (STARSS) randomised control trial sought to evaluate the acceptability of SMS for AEFI surveillance. MethodsThe primary STARSS study was a multi-centre RCT evaluating the efficacy of repeated SMS prompts for AEFI surveillance with participants being adult vaccinees or parents of children receiving any vaccine. This nested study enrolled primary RCT participants who completed a detailed computer assisted telephone interview to determine their attitudes towards SMS-based surveillance and ascertain their knowledge and attitudes toward vaccine safety, efficacy, data privacy and use of electronic health records. Attitudes to surveillance and related behaviour were used as measures of acceptability. Results20% (1200/6555) of the participants were enrolled and 1139 completed the full-length questionnaire. 96% indicated that SMS-based surveillance after immunisation to check the safety of the vaccine “should be done” but 62% of all respondents said it should be done but consent should be sought first. Neither vaccine safety attitudes nor attitudes toward privacy were associated with opposition to SMS-based surveillance. In terms of SMS related behaviour demographic rather than attitudinal factors were associated with non-compliance. ConclusionOverall, the attitude towards SMS-based surveillance was very favourable. Experiencing the SMS surveillance has the effect of reducing opposition to an SMS surveillance system, and at the same time increasing the likelihood of a preference for prior consent. Detection of a vaccine safety signal could be impeded in particular demographic groups who are non-compliant and we should undertake further research to understand why these groups are non-compliant and how this can be improved.

Web-Based Self-Management for Patients With Lymphoma: Assessment of the Reach of Intervention of a Randomized Controlled Trial.

BackgroundRandomized controlled trials (RCTs) often provide accurate estimates of the internal validity of an intervention but lack information on external validity (generalizability). We conducted an RCT on the effectiveness of a self-management intervention among patients with lymphoma in a population-based setting.ObjectiveThe objectives of the current study were to describe the proportion of RCT participants compared to all patients invited to participate, and compare sociodemographic and clinical characteristics of RCT participants with all respondents, all patients invited to participate, and all patients selected from the Netherlands Cancer Registry (NCR) to determine the reach of the intervention. An additional objective was to assess differences on RCT outcome variables between RCT and paper respondents.MethodsPatients with lymphoma or chronic lymphocytic leukemia ≥18 years old at diagnosis from 13 hospitals in the Netherlands were selected from the population-based NCR, which routinely collects data on sociodemographic and clinical characteristics. Eligible patients were invited to participate in an RCT and complete a questionnaire. Web-based completion determined RCT enrollment, whereas paper respondents were followed observationally.ResultsA total of 1193 patients were selected from the NCR, 892 (74.77%) of whom were invited to participate in the trial by their hematologist after verifying eligibility. Among those invited, 25.4% (227/892) completed the web-based questionnaire and were enrolled in the RCT. The RCT participants were younger and there was a higher proportion of men than nonparticipants (P<.001). In addition, 25.7% (229/892) of those invited opted to participate in the paper-based observational follow-up study. Compared with paper respondents, RCT participants were younger (P<.001), with a higher proportion of men (P=.002), and had higher education levels (P=.02). RCT participants more often wanted to receive all available information on their disease (P<.001), whereas paper respondents reported higher levels of emotional distress (P=.009).ConclusionsFrom a population-based sample of eligible patients, the participation rate in the RCT was approximately 25%. RCT participants may not be representative of the target population because of different sociodemographic and clinical characteristics. Since RCT participants represent a minority of the target population, RCT results should be interpreted with caution as patients in the RCT may be those least in need of a self-management intervention.Trial RegistrationNetherlands Trial Register NTR5953; https://www.trialregister.nl/trial/5790

Treatment effects may remain the same even when trial participants differed from the target population

ObjectivesRandomized controlled trials (RCTs) have been criticized for lacking external validity. We assessed whether a trial in people with type I diabetes mellitus mirrored the wider population and applied sample-weighting methods to assess the impact of differences on our trial's findings. Study Design and SettingThe Relative Effectiveness of Pumps over MDI and Structured Education trial was nested within a large UK cohort capturing demographic, clinical, and quality of life data for people with type I diabetes mellitus undergoing structured diabetes-specific education. We first assessed whether our RCT participants were comparable with this cohort using propensity score modeling. After this, we reweighted the trial population to better match the wider cohort and re-estimated the treatment effect. ResultsTrial participants differed from the cohort in regard to sex, weight, HbA1c, and also quality of life and satisfaction with current treatment. Nevertheless, the treatment effects derived from alternative model weightings were similar to that of the original RCT. ConclusionOur RCT participants differed in composition to the wider population, but the original findings were unaffected by sampling adjustments. We encourage investigators take steps to address criticisms of generalizability but doing so is problematic; external data, even if available, may contain limited information and analyses can be susceptible to model misspecification.

Glucocorticoid-trials in rheumatoid arthritis mostly study representative real-world patients: A systematic review and meta-analysis

ObjectiveRandomized controlled trials (RCTs) are considered the gold standard in clinical research due to credible causality. Their results, however, may not be generalizable to real-world populations. While glucocorticoids (GCs) remain a mainstay of rheumatoid arthritis (RA) treatment, it is unclear whether the results of GC-RCTs are generalizable to current real-world RA patients. MethodsMEDLINE was searched for RCTs and, as comparators, cohort studies (CSs) in RA evaluating systemic GCs. Random-effects meta-analyses were performed for descriptive baseline characteristics (including general demographics, comorbidities, and disease activity) that have been shown to be able to modify the benefit-risk-ratio of various RA therapeutics. These meta-analyses were stratified by study type (RCT and CS). Stratified estimates were subsequently compared. Further sensitivity analyses were performed stratifying by disease duration. Results56 RCTs (7053 participants) and 10 CSs (14,688 participants) were included. 12 characteristics were reported frequently enough to allow for comparative analysis. In 10/12 characteristics (83%), RCT estimates did not appear to differ from CS estimates. However, RCT participants were younger (-4.7 years [95% CI -7.2 to -2.1]; p < 0.001) and had higher erythrocyte sedimentation rates (11.8 mm/h [5.7 to 17.8]; p < 0.001) than CS participants. Comorbidities could not be assessed due to insufficient reporting. ConclusionOur findings suggest that evidence from GC trials in RA is of acceptable generalizability to current real-world patients – especially compared to findings from biologic agents in RA. However, RCT participants were younger than real-world patients, potentially limiting the generalizability of trial results to elderly patients. Systematic review registrationPROSPERO (CRD42019134675)

Physical Activity Levels Are Low in Inoperable Lung Cancer: Exploratory Analyses from a Randomised Controlled Trial.

Background: In inoperable lung cancer, evidence is limited regarding physical activity (PA) and associations with other outcomes. Aims: in the usual care (UC) group of an RCT to (1) explore whether baseline PA was associated with improved follow-up outcomes, (2) identify baseline variables associated with higher follow-up PA and in all RCT participants, to (3) analyse patterns of objectively measured PA, and (4) report on characteristics of those who were able to maintain or increase PA levels. Methods: exploratory analyses of an assessor-blinded RCT. Outcomes, assessed at baseline, nine weeks and six months, included PA (seven-days of accelerometry), six-minute walk distance (6MWD), muscle strength, symptoms, mood and health-related quality of life (HRQoL). Results: 92 participants were randomised, 80 completed baseline accelerometry (39 intervention group (IG), 41 UC), characteristics: mean (SD) age 63.0 (12.3) years, 56% male, 51% stage IV disease. Baseline PA: median (IQR) steps/day 2859.6 (2034.0–3849.2) IG versus 3195.2 (2161.2–4839.0) UC. Associations between baseline PA and six-month outcomes were significant for HRQoL and 6MWD. PA at six months was significantly associated with baseline age, 6MWD and quadriceps strength. Between-group change score (steps/day) mean differences (95% CI) at nine weeks (174.5 (−1504.7 to 1853.7), p = 0.84) and six months (574.0 (−1162.3 to 2310.3), p = 0.52). Conclusions: further research is required to determine patient subgroups deriving the greatest benefits from PA interventions.