Characteristics Of Trial Participants Research Articles

Racial/ethnic distribution of participants in NRG oncology clinical trials: 2014-2023.

e13706 Background: External validity and applicability of clinical research relies upon characteristics of trial participants matching those of the respective disease groups in the general population. Understanding the racial/ethnic distribution of patients enrolled in recent US-based, federally sponsored Phase II and III clinical trials could inform strategies to further align characteristics of trial participants with those of disease group populations. As such, we report the racial/ethnic distribution of participants in NRG Oncology studies during 2014-2023 and compare the distribution to that from the Surveillance, Epidemiology, and End Results (SEER) program data during 2014-2020 (most recent data available). Methods: Proportions of self-reported race/ethnicity were summarized for the 33,370 trial participants enrolled since Mar 1, 2014 (NRG Oncology inception) to therapeutic, symptoms management, and other interventional trials. SEER proportions were used to benchmark NRG trials for representativeness of disease burden in the population. Results: Among NRG trial participants, 71.5% were non-Hispanic (NH) White, 9.7% NH Black, 4.9% Hispanic, and 7.8% N-H Asian (Table). Examining distributions within selected cancer sites relative to cancer proportional incidence in 2014-2020 SEER data, NRG accrual to prostate, lung, cervix, and breast cancer trials is commensurate with observed disease burden for NH Blacks and modestly lower for Asians. For other sites shown, representation was 2 to 5 percentage points lower than SEER frequencies for Blacks and Asians. For all sites, accrual of individuals of Hispanic background was lower than that reported in SEER. As the NRG trials do not reflect sampling across stages and other features of a given cancer in the population, further analysis to be presented will consist of more detailed breakdowns of trial participant disease-specific cancer stage and tumor subtype and comparison to relevant observations from the 2014-2020 SEER database. Conclusions: This high-level comparison of the racial/ethnic distribution of NRG trial participants provides supportive information for population representative enrollment in several cancer sites, but also identifies opportunities to improve enrollment diversity to represent more closely the respective affected population. Areas of success identified merit further investigation to understand if there are best practices which may be applied more broadly towards expanding access to federally funded clinical trials. [Table: see text]

Are Orthopaedic Clinical Trials Linguistically and Culturally Diverse? A Systematic Review.

Underrepresentation and misrepresentation of historically underrepresented populations in randomized controlled trials (RCTs) may have implications for the validity of research results and their application for diverse populations. To evaluate the representation of historically linguistically, racially, and ethnically underrepresented participants in orthopaedic randomized controlled trials (RCTs) and to assess the use of translated and culturally adapted patient reported outcome measures (PROMs). Separate and comprehensive literature searches of PubMed, Web of Science, and Embase databases were performed to identify RCTs utilizing PROMs between the years 2012 - 2022 among the top five highest 5-year impact factor orthopaedic journals according to the 2021 Journal Citation Reports database. The primary outcomes of interest included reporting of linguistic, racial and ethnic demographic characteristics of trial participants and the utilization of translated PROMs. The methodological quality of each clinical trial was assessed using the Jadad Criteria. 230 RCTs met inclusion criteria. The language of participants was reported in 14% of trials and in 17% of trials when searching both the published text and clinical trial registration information. In addition, race and/or ethnicity was reported in 11% of trials, and the use of translated PROMs was reported in 7% of trials. Among the six multinational studies, none reported the language of the study population nor the use of translated PROMs. Notably, four studies (2%) reported utilizing culturally adapted PROMs. The average Jadad score was 3.07. Participant language, race, and ethnicity are infrequently reported in orthopaedic clinical trials, potentially limiting the application and interpretation of study results. Similarly, the linguistic and cultural adaptation of PROMs utilized are often not reported, which also limits interpretations of the validity and generalizability of orthopedic study results. Researchers and journals should promote standard reporting of demographic data and methods of PROM adaptation to ensure results are generalizable to diverse patient populations. III.

Generalizability of Randomized Clinical Trial Outcomes for Diabetes Control Resulting From Bariatric Surgery.

To assess the external validity of randomized controlled trials (RCTs) of bariatric surgical treatment on diabetes control. Multisite RCTs provide the strongest evidence supporting clinical treatments and have the greatest internal validity. However, characteristics of trial participants may not be representative of patients receiving treatment in the real world. There is a need to assess how the results of RCTs generalize to all contemporary patient populations undergoing treatments. All patients undergoing sleeve gastrectomy at University of California Los Angeles (UCLA) between January 8, 2018 and May 19, 2023 had their baseline characteristics, weight change, and diabetes control compared with those enrolled in the surgical treatment and medications potentially eradicate diabetes efficiently (STAMPEDE) and diabetes surgery study (DSS) RCTs of bariatric surgery's effect on diabetes control. Weight loss and diabetes control were compared between UCLA patients who did and did not fit the entry criteria for these RCTs. Only 65 (17%) of 387 patients with diabetes fulfilled the eligibility criteria for STAMPEDE, and 29 (7.5%) fulfilled the criteria for DSS due to being older, having higher body mass index, and lower HbA1c. UCLA patients experienced slightly less weight loss than patients in the RCTs but had similar diabetes control. The 313 (81%) patients not eligible for study entry into either RCT had similar long-term diabetes control as those who were eligible for the RCTs. Even though only a very small proportion of patients undergoing bariatric surgery met the eligibility criteria for the 2 major RCTs, most patients in this contemporary cohort had similar outcomes. Diabetes outcomes from STAMPEDE and DSS generalize to most patients undergoing bariatric surgery for diabetes control.

Comparing Lung Cancer Screening Strategies in a Nationally Representative US Population Using Transportability Methods for the National Lung Cancer Screening Trial

The National Lung Screening Trial (NLST) found that screening for lung cancer with low-dose computed tomography (CT) reduced lung cancer-specific and all-cause mortality compared with chest radiography. It is uncertain whether these results apply to a nationally representative target population. To extend inferences about the effects of lung cancer screening strategies from the NLST to a nationally representative target population of NLST-eligible US adults. This comparative effectiveness study included NLST data from US adults at 33 participating centers enrolled between August 2002 and April 2004 with follow-up through 2009 along with National Health Interview Survey (NHIS) cross-sectional household interview survey data from 2010. Eligible participants were adults aged 55 to 74 years, and were current or former smokers with at least 30 pack-years of smoking (former smokers were required to have quit within the last 15 years). Transportability analyses combined baseline covariate, treatment, and outcome data from the NLST with covariate data from the NHIS and reweighted the trial data to the target population. Data were analyzed from March 2020 to May 2023. Low-dose CT or chest radiography screening with a screening assessment at baseline, then yearly for 2 more years. For the outcomes of lung-cancer specific and all-cause death, mortality rates, rate differences, and ratios were calculated at a median (25th percentile and 75th percentile) follow-up of 5.5 (5.2-5.9) years for lung cancer-specific mortality and 6.5 (6.1-6.9) years for all-cause mortality. The transportability analysis included 51 274 NLST participants and 685 NHIS participants representing the target population (of approximately 5 700 000 individuals after survey-weighting). Compared with the target population, NLST participants were younger (median [25th percentile and 75th percentile] age, 60 [57 to 65] years vs 63 [58 to 67] years), had fewer comorbidities (eg, heart disease, 6551 of 51 274 [12.8%] vs 1 025 951 of 5 739 532 [17.9%]), and were more educated (bachelor's degree or higher, 16 349 of 51 274 [31.9%] vs 859 812 of 5 739 532 [15.0%]). In the target population, for lung cancer-specific mortality, the estimated relative rate reduction was 18% (95% CI, 1% to 33%) and the estimated absolute rate reduction with low-dose CT vs chest radiography was 71 deaths per 100 000 person-years (95% CI, 4 to 138 deaths per 100 000 person-years); for all-cause mortality the estimated relative rate reduction was 6% (95% CI, -2% to 12%). In the NLST, for lung cancer-specific mortality, the estimated relative rate reduction was 21% (95% CI, 9% to 32%) and the estimated absolute rate reduction was 67 deaths per 100 000 person-years (95% CI, 27 to 106 deaths per 100 000 person-years); for all-cause mortality, the estimated relative rate reduction was 7% (95% CI, 0% to 12%). Estimates of the comparative effectiveness of low-dose CT screening compared with chest radiography in a nationally representative target population were similar to those from unweighted NLST analyses, particularly on the relative scale. Increased uncertainty around effect estimates for the target population reflects large differences in the observed characteristics of trial participants and the target population.

Critical reading of cardiovascular trials with neutral or negative findings

Randomized controlled trials showing a significant benefit are met with enthusiasm because they may change the standard of care for patients who share the clinical and pathophysiologic characteristics of trial participants. Nonetheless, a well-designed and fully executed trial with neutral or negative findings also represents a critically important investigation deserving careful scientific scrutiny. In this paper we propose a 10-step approach to the interpretation of neutral or negative trials to exclude important methodological issues before concluding that the treatment really does not work. We will discuss this approach using the most classic trials of the past and some notable examples among superiority trials (mostly phase 3 trials) published over the last years.

T1dCteGui: A User-Friendly Clinical Trial Enrichment Tool to Optimize T1D Prevention Studies by Leveraging AI/ML Based Synthetic Patient Population.

Whereas islet autoantibodies (AAs) are well-established risk factors for developing type 1 diabetes (T1D), there is a lack of biomarkers endorsed by regulators to enrich clinical trial populations for those at risk of developing T1D. As such, the development of therapies that delay or prevent the onset of T1D remains challenging. To address this drug development need, the Critical Path Institute's T1D Consortium (T1DC) acquired patient-level data from multiple observational studies and used a model-based approach to evaluate the utility of islet AAs as enrichment biomarkers in clinical trials. An accelerated failure time model was developed, discussed in our previous publication, which provided the underlying evidence required to receive a qualification opinion for islet AAs as enrichment biomarkers from the European Medicines Agency (EMA) in March 2022. To further democratize the use of the model for scientists and clinicians, we developed a Clinical Trial Enrichment Graphical User Interface. The interactive tool allows users to specify trial participant characteristics, including the percentage of participants with a specific AA combination. Users can specify ranges for participant baseline age, sex, blood glucose measurement from the 120-minute timepoints of an oral glucose tolerance test, and HbA1c. The tool then applies the model to predict the mean probability of a T1D diagnosis for that trial population and renders the results to the user. To ensure adequate data privacy and to make the tool open-source, a deep learning-based generative model was used to generate a cohort of synthetic subjects that underpins the tool.

Clinical comparison between trial participants and potentially eligible patients using electronic health record data: A generalizability assessment method

ObjectiveTo present a generalizability assessment method that compares baseline clinical characteristics of trial participants (TP) to potentially eligible (PE) patients as presented in their electronic health record (EHR) data while controlling for clinical setting and recruitment period. MethodsFor each clinical trial, a clinical event was defined to identify patients of interest using available EHR data from one clinical setting during the trial’s recruitment timeframe. The trial’s eligibility criteria were then applied and patients were separated into two mutually exclusive groups: (1) TP, which were patients that participated in the trial per trial enrollment data; (2) PE, the remaining patients. The primary outcome was standardized differences in clinical characteristics between TP and PE per trial. A standardized difference was considered prominent if its absolute value was greater than or equal to 0.1. The secondary outcome was the difference in mean propensity scores (PS) between TP and PE per trial, in which the PS represented prediction for a patient to be in the trial. Three diverse trials were selected for illustration: one focused on hepatitis C virus (HCV) patients receiving a liver transplantation; one focused on leukemia patients and lymphoma patients; and one focused on appendicitis patients. ResultsFor the HCV trial, 43 TP and 83 PE were found, with 61 characteristics evaluated. Prominent differences were found among 69% of characteristics, with a mean PS difference of 0.13. For the leukemia/lymphoma trial, 23 TP and 23 PE were found, with 39 characteristics evaluated. Prominent differences were found among 82% of characteristics, with a mean PS difference of 0.76. For the appendicitis trial, 123 TP and 242 PE were found, with 52 characteristics evaluated. Prominent differences were found among 52% of characteristics, with a mean PS difference of 0.15. ConclusionsDifferences in clinical characteristics were observed between TP and PE among all three trials. In two of the three trials, not all of the differences necessarily compromised trial generalizability and subsets of PE could be considered similar to their corresponding TP. In the remaining trial, lack of generalizability appeared present, but may be a result of other factors such as small sample size or site recruitment strategy. These inconsistent findings suggest eligibility criteria alone are sometimes insufficient in defining a target group to generalize to. With caveats in limited scalability, EHR data quality, and lack of patient perspective on trial participation, this generalizability assessment method that incorporates control for temporality and clinical setting promise to better pinpoint clinical patterns and trial considerations.

Examination of exclusion criteria in total knee arthroplasty rehabilitation trials: influence on the application of evidence in day-to-day practice.

Total knee arthroplasty (TKA) rehabilitation trials use exclusion criteria, which may limit their generalizability in practice. We investigated whether patients seen in routine practice who meet common exclusion criteria recover differently from TKA compared to research-eligible patients. We hypothesized that research-ineligible patients would demonstrate poorer average postoperative function and slower rate of functional recovery compared to research-eligible patients. Patient characteristics and exclusion criteria were extracted and summarized from trials included in the three most recent systematic reviews of TKA rehabilitation. Trial participant characteristics were compared to a clinical dataset of patient outcomes collected in routine TKA rehabilitation. Where possible, individual exclusion criterion from the trials were applied to the clinical dataset to determine "eligible" and "ineligible" groups for research participation. Postoperative functional outcomes including the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and Timed Up and Go (TUG) were compared between "eligible" and "ineligible" groups using mixed effects models. 2,528 participants from 27 trials were compared to 474 patients from the clinical dataset. Research participants were older, with lower Body Mass Index than patients in the clinical dataset. Many patients in the clinical dataset would be "ineligible" for research participation based upon common exclusion criteria from the trials. Differences were observed in average postoperative functioning between some "eligible" and "ineligible" groups in the clinical dataset. However, no differences were observed in functional recovery rate between groups, except for patients with diabetes whose TUG recovered more slowly than their "eligible" counterparts. Many patients in the clinical dataset were "ineligible" for research participation based upon common TKA rehabilitation trial exclusion criteria. However, the postoperative recovery rate did not differ between "eligible" and "ineligible" groups based on individual exclusion criterion-except for individuals with diabetes. This suggests that both clinical and research populations may recover similarly from TKA.

Do interventions to improve adherence to antiretroviral therapy recognise diversity? A systematic review

ABSTRACT People living with HIV (PLWH) are often culturally and linguistically diverse populations; these differences are associated with differing barriers to antiretroviral therapy (ART) adherence. Cultural competence measures the extent to which trial design recognises this diversity. This systematic review aimed to determine whether adherence trial participants represent the diversity of PLWH. Randomised Controlled Trials in Organisation for Economic Co-operation and Development countries to improve ART adherence were eligible. We searched MEDLINE, EMBASE, and Cochrane Database of Systematic Reviews. For all included trials, we searched for their development, testing and evaluation studies. We compared trial participant characteristics with nationally reported PLWH data. We appraised trial cultural competence against ten criteria; scoring each criterion as 0, 1 or 2 indicating cultural blindness, pre-competence or competence respectively. For 80 included trials, a further 13 studies presenting development/testing/evaluation data for the included trials were identified. Only one of the 80 included studies reported trial participants representative of the country’s population of PLWH. The median (IQ) cultural competence score was 2.5 (1.0, 4.0) out of 20. HIV adherence trial participants are not reflective of the population with HIV, which may be due to limited adoption of culturally competent research methods.

P1283BASELINE CHARACTERISTICS IN THE “IPACK-HD” STUDY (INHIBIT PROGRESSION OF CORONARY ARTERY CALCIFICATION WITH VITAMIN K IN HEMODIALYSIS PATIENTS): A PHASE 2, MULTI-CENTRE, DOUBLE-BLIND, RANDOMIZED, PLACEBO-CONTROLLED PILOT TRIAL

Abstract Background and Aims The leading cause of mortality for patients with end-stage kidney disease (ESKD) is cardiovascular disease (CVD). This is due, in part, to vascular calcification (VC) where calcium becomes deposited within arterial walls causing narrowing of the arteries and altering their flexibility. Matrix Gla protein (MGP), a vitamin k-dependent protein, is a key local inhibitor of VC and becomes up-regulated adjacent to sites of calcification. There is a very high prevalence of vitamin K deficiency in patients across the chronic kidney disease (CKD) spectrum and vitamin K has been shown to prevent VC in experimental models. To date, no trial has examined whether vitamin K supplementation prevents the progression of coronary artery calcification in patients with ESKD, a group in which high risk has been established. The aim of the iPACK-HD pilot study is to determine whether a trial to determine whether vitamin K has a favourable effect on coronary artery calcium (CAC) scores in patients with ESKD is feasible. Method The iPACK-HD pilot trial is a phase 2 multi-centre, double-blind, randomized, placebo-controlled clinical trial conducted in three sites (Kingston, Ottawa and London) in Ontario, Canada. Adult patients with ESKD on chronic dialysis with a baseline CAC score of ≥30 Agatston units (AUs) are randomized to receive 10 mg of vitamin K1 or matching placebo administered post-hemodialysis 3x/week for a total of 12 months. Exclusions include medical conditions that require anticoagulation and a history of either coronary artery bypass, grafting or stenting. Randomization is stratified based on diabetes and study centre. Baseline CAC scores are determined by computed tomography (CT) and demographic and laboratory data at study entry are obtained by participant interview and medical chart review. Results A total of 85 participants are randomized into this trial. Baseline characteristics of trial participants are reported as mean ± SD, median [IQR], or %. The mean age is 63 ± 13 years. There are a higher proportion of males (57%) than females and whites (85%) compared to all other ethnicities. Forty-four percent of participants have diabetes and 77% have hypertension. Dialysis vintage is 0.9 [0.4,2.7] years. Most participants take calcium-based phosphate binders (89%) and over half of participants take an HMG-CoA reductase inhibitor (53%) or vitamin D (61%). Clinical laboratory values are presented in Table 1. Total median CAC and volume calcium scores are 587 [252,1416] AUs and 482 [206,1170] mm3, respectively. Sixty-five (76%) participants had a study exit CT scan performed upon completion of the study. Of 156 doses, a median of 150 [123,155] were received and 2 [1,6] were missed. Conclusion Participants in the iPACK-HD study have a high burden of calcification but are similar in baseline characteristics to the Canadian hemodialysis population. Loss to trial completion is 24%, but the most frequent reason is kidney transplantation. Adherence to study drug is very high with few reported side effects.

Women's Participation in Cardiovascular Clinical Trials From 2010 to 2017.

Cardiovascular disease is the leading cause of death among women worldwide, yet, women have historically been underrepresented in cardiovascular trials. We systematically assessed the participation of women in completed cardiovascular trials registered in ClinicalTrials.gov between 2010 and 2017, and extracted publicly available information including disease type, sponsor type, country, trial size, intervention type, and the demographic characteristics of trial participants. We calculated the female-to-male ratio for each trial and determined the prevalence-adjusted estimates for participation of women by dividing the percentage of women among trial participants by the percentage of women in the disease population (participation prevalence ratio; a ratio of 0.8 to 1.2 suggests comparable prevalence and good representation). We identified 740 completed cardiovascular trials including a total of 862 652 adults, of whom 38.2% were women. The median female-to-male ratio of each trial was 0.51 (25th quartile, 0.32; 75th quartile, 0.90) overall and varied by age group (1.02 in ≤55 year old group versus 0.40 in the 61- to 65-year-old group), type of intervention (0.44 for procedural trials versus 0.78 for lifestyle intervention trials), disease type (0.34 for acute coronary syndrome versus 3.20 for pulmonary hypertension), region (0.45 for Western Pacific versus 0.55 for the Americas), funding/sponsor type (0.14 for government-funded versus 0.73 for multiple sponsors), and trial size (0.56 for smaller [n≤47] versus 0.49 for larger [n≥399] trials). Relative to their prevalence in the disease population, participation prevalence ratio was higher than 0.8 for hypertension, pulmonary arterial hypertension and lower (participation prevalence ratio 0.48 to 0.78) for arrhythmia, coronary heart disease, acute coronary syndrome, and heart failure trials. The most recent time period (2013 to 2017) saw significant increases in participation prevalence ratios for stroke (P=0.007) and heart failure (P=0.01) trials compared with previous periods. Among cardiovascular trials in the current decade, men still predominate overall, but the representation of women varies with disease and trial characteristics, and has improved in stroke and heart failure trials.

Participant-level characteristics differ by recruitment setting when evaluating a behavioral intervention targeting adolescents with asthma

Objective The recruitment setting plays a key role in the evaluation of behavioral interventions. We evaluated a behavioral intervention for urban adolescents with asthma in three randomized trials conducted separately in three different settings over the course of 8 years. We hypothesized that characteristics of trial participants recruited from the ED and clinic settings would be significantly different from that of youth participating in the school-based trials. The intervention evaluated was Puff City, a web-based program that uses tailoring to improve asthma management behaviors. Methods The present analysis includes youth aged 13–19 years who reported a physician diagnosis of asthma and symptoms at trial baseline. In the three trials, all participants were randomized post-baseline to a web-based, tailored intervention (treatment) or generic web-based asthma education (control). Results Compared to school-based trial participants, ED participants had significantly more acute-care visits for asthma (p < 0.001) and more caregiver depression (p < 0.001). Clinic-based participants were more likely to have computer/ internet access than participants from the school-based trial (p < 0.001). Both ED and clinic participants were more likely to report controller medication (p's < 0.001) and higher teen emotional support (p's < 0.01) when compared to the schools, but were less likely to report Medicaid (p's < 0.014) and exposure to environmental tobacco smoke (p < 0.001). Conclusion Compared to participants in the school-based trials, participants recruited from ED and clinic settings differed significantly in terms of healthcare use, as well as psychosocial and sociodemographic factors. These factors can inform intervention content, and may impact external validity of behavioral interventions for asthma.

Trial design and baseline characteristics of CaLIPSO: a randomized, double-blind placebo-controlled trial of SNF472 in patients receiving haemodialysis with cardiovascular calcification.

BackgroundThe objective of CaLIPSO, a Phase 2b, randomized, double-blind, placebo-controlled clinical trial, is to test the hypothesis that myo-inositol hexaphosphate (SNF472) attenuates the progression of cardiovascular calcification in patients receiving maintenance haemodialysis. Here we report the trial design and baseline characteristics of trial participants.MethodsAdult patients on maintenance haemodialysis (≥6 months) with an Agatston coronary artery calcium score, as measured by a multidetector computed tomography scanner, of 100–3500 U were enrolled. Patients were stratified by Agatston score (100–<400, 400–1000 or >1000 U) and randomized in a 1:1:1 ratio to receive placebo, SNF472 300 mg or SNF472 600 mg administered intravenously three times weekly during each haemodialysis session.ResultsOverall, 274 patients were randomized. The mean age of trial participants was 63.6 (standard deviation 8.9) years and 39% were women. The coronary artery, aorta and aortic valve median (25th-75th percentile) Agatston scores at baseline were 730 U (315–1435), 1728 U (625–4978) and 103 U (31–262), respectively, and the median (25th–75th percentile) calcium volume scores at baseline were 666 (310–1234), 1418 (536–4052) and 107 (38–278), respectively. Older age and diabetes mellitus were associated with higher calcium scores at baseline.ConclusionsThe CaLIPSO trial enrolled patients on haemodialysis with pre-existent cardiovascular calcification to test the hypothesis that SNF472 attenuates its progression in the coronary arteries, aorta and aortic valve.

Cost-effectiveness of Hepatitis C Virus Treatment Models for People Who Inject Drugs in Opioid Agonist Treatment Programs.

Many people who inject drugs in the United States have chronic hepatitis C virus (HCV). On-site treatment in opiate agonist treatment (OAT) programs addresses HCV treatment barriers, but few evidence-based models exist. We evaluated the cost-effectiveness of HCV treatment models for OAT patients using data from a randomized trial conducted in Bronx, New York. We used a decision analytic model to compare self-administered individual treatment (SIT), group treatment (GT), directly observed therapy (DOT), and no intervention for a simulated cohort with the same demographic characteristics of trial participants. We projected long-term outcomes using an established model of HCV disease progression and treatment (hepatitis C cost-effectiveness model: HEP-CE). Incremental cost-effectiveness ratios (ICERs) are reported in 2016 US$/quality-adjusted life years (QALY), discounted 3% annually, from the healthcare sector and societal perspectives. For those assigned to SIT, we projected 89% would ever achieve a sustained viral response (SVR), with 7.21 QALYs and a $245 500 lifetime cost, compared to 22% achieving SVR, with 5.49 QALYs and a $161 300 lifetime cost, with no intervention. GT was more efficient than SIT, resulting in 0.33 additional QALYs and a $14 100 lower lifetime cost per person, with an ICER of $34 300/QALY, compared to no intervention. DOT was slightly more effective and costly than GT, with an ICER > $100 000/QALY, compared to GT. In probabilistic sensitivity analyses, GT and DOT were preferred in 91% of simulations at a threshold of <$100 000/QALY; conclusions were similar from the societal perspective. All models were associated with high rates of achieving SVR, compared to standard care. GT and DOT treatment models should be considered as cost-effective alternatives to SIT.

A Demographic Analysis of Racial/Ethnic Minority Enrollment Into HVTN Preventive Early Phase HIV Vaccine Clinical Trials Conducted in the United States, 2002-2016.

Racial/ethnic minority communities in the United States are overrepresented among new HIV diagnoses, yet their inclusion in preventive HIV vaccine clinical trials is inadequate. An analysis of enrollment demographic characteristics from US preventive HIV vaccine clinical trials from 1988 through 2002 showed that enrollment of racial/ethnic minority groups increased. We analyzed enrollment in preventive HIV vaccine clinical trials from 2002 through 2016 and compared our data with data from the previous study, described demographic characteristics of trial participants, and assessed how well this distribution reflected the racial/ethnic distribution of new HIV diagnoses in the United States. We examined data on demographic characteristics from 43 Phase 1 and Phase 2A preventive HIV vaccine clinical trials conducted in the United States and compared the results with those of the previous study. We also compared racial/ethnic distributions from 2011 through 2015 with Centers for Disease Control and Prevention data on the number of new HIV diagnoses during the same period. Of 3469 participants, 1134 (32.7%) identified as a racial/ethnic minority, a 94% increase from the previous period (634/3731; 17.0%). Percentage annual enrollment of all racial/ethnic minority participants fluctuated from 17% to 53% from mid-2002 to 2016. Percentages of new HIV diagnoses among the general population were 1.9 to 2.9 times the percentage enrollment of black participants and 1.3 to 6.6 times the percentage enrollment of Hispanic/Latino participants in clinical trials for the same period. Although enrollment of racial/ethnic minority groups into HIV vaccine clinical trials has increased, it is not proportional to the number of new HIV diagnoses among these groups. To enhance recruitment of racial/ethnic minority groups, the HIV Vaccine Trials Network has prioritized community partnerships and invested resources into staff training.

Lessons learned from the London Exercise and Pregnant (LEAP) Smokers randomised controlled trial process evaluation: implications for the design of physical activity for smoking cessation interventions during pregnancy

BackgroundThe challenges of delivering interventions for pregnant smokers have been poorly documented. Also, the process of promoting a physical activity intervention for pregnant smokers has not been previously recorded. This study describes the experiences of researchers conducting a randomised controlled trial of physical activity as an aid to smoking cessation during pregnancy and explores how the effectiveness of future interventions could be improved.MethodsTwo focus groups, with independent facilitators, were conducted with six researchers who had enrolled pregnant smokers in the LEAP trial, provided the interventions, and administered the research measures. Topics included recruitment, retention and how the physical activity intervention for pregnant smokers was delivered and how it was adapted when necessary to suit the women. The focus groups were audio-recorded, transcribed verbatim and subjected to thematic analysis.ResultsFive themes emerged related to barriers or enablers to intervention delivery: (1) nature of the intervention; (2) personal characteristics of trial participants; (3) practical issues; (4) researchers’ engagement with participants; (5) training and support needs. Researchers perceived that participants may have been deterred by the intensive and generic nature of the intervention and the need to simultaneously quit smoking and increase physical activity. Women also appeared hampered by pregnancy ailments, social deprivation, and poor mental health. Researchers observed that their status as health professionals was valued by participants but it was challenging to maintain contact with participants. Training and support needs were identified for dealing with pregnant teenagers, participants’ friends and family, and post-natal return to smoking.ConclusionsFuture exercise interventions for smoking cessation in pregnancy may benefit by increased tailoring of the intervention to the characteristics of the women, including their psychological profile, socio-economic background, pregnancy ailments and exercise preferences. Delivering an effective physical activity intervention for smoking cessation in pregnancy may require more comprehensive training for those delivering the intervention, particularly with regard to dealing with teenage smokers and smokers’ friends and family, as well as for avoiding post-natal return to smoking.Trial registrationISRCTN48600346, date of registration: 21/07/2008.

Computer-aided assessment of the generalizability of clinical trial results

BackgroundThe effects of an intervention on patients from populations other than that included in a trial may vary as a result of differences in population features, treatment administration, or general setting. Determining the generalizability of a trial to a target population is important in clinical decision making at both the individual practitioner and policy-making levels. However, awareness to the challenges associated with the assessment of generalizability of trials is low and tools to facilitate such assessment are lacking. MethodsWe review the main factors affecting the generalizability of a clinical trial results beyond the trial population. We then propose a framework for a standardized evaluation of parameters relevant to determining the external validity of clinical trials to produce a “generalizability score”. We then apply this framework to populations of patients with heart failure included in trials, cohorts and registries to demonstrate the use of the generalizability score and its graphic representation along three dimensions: participants’ demographics, their clinical profile and intervention setting. We use the generalizability score to compare a single trial to multiple “target” clinical scenarios. Additionally, we present the generalizability score of several studies with regard to a single “target” population. ResultsSimilarity indices vary considerably between trials and target population, but inconsistent reporting of participant characteristics limit head-to-head comparisons. ConclusionWe discuss the challenges involved in performing automatic assessment of trial generalizability at scale and propose the adoption of a standard format for reporting the characteristics of trial participants to enable better interpretation of their results.

Baseline Characteristics and Generalizability of Participants in an Internet Smoking Cessation Randomized Trial.

The potential for sampling bias in Internet smoking cessation studies is widely recognized. However, few studies have explicitly addressed the issue of sample representativeness in the context of an Internet smoking cessation treatment trial. The purpose of the present study is to examine the generalizability of participants enrolled in a randomized controlled trial of an Internet smoking cessation intervention using weighted data from the National Health Interview Survey (NHIS). A total of 5290 new users on a smoking cessation website enrolled in the trial between March 2012 and January 2015. Descriptive statistics summarized baseline characteristics of screened and enrolled participants, and multivariate analysis examined predictors of enrollment. Generalizability analyses compared demographic and smoking characteristics of trial participants to current smokers in the 2012-2014 waves of NHIS (n = 19,043) and to an NHIS subgroup based on Internet use and cessation behavior (n = 3664). Effect sizes were obtained to evaluate the magnitude of differences across variables. Predictors of study enrollment were age, gender, race, education, and motivation to quit. Compared to NHIS smokers, trial participants were more likely to be female, college educated, and daily smokers and to have made a quit attempt in the past year (all effect sizes 0.25-0.60). In comparisons with the NHIS subgroup, differences in gender and education were attenuated, while differences in daily smoking and smoking rate were amplified. Few differences emerged between Internet trial participants and nationally representative samples of smokers, and all were in expected directions. This study highlights the importance of assessing generalizability in a focused and specific manner. CLINICALTRIALS.GOV: #NCT01544153.

A case study of SMART attributes: a qualitative assessment of generalizability, retention rate, and trial quality.

BackgroundPersonalizing medical care is becoming increasingly popular, particularly mental health care. There is growing interest in formalizing medical decision making based on evolving patient symptoms in an evidence-based manner. To determine optimal sequencing of treatments, the sequences themselves must be studied; this may be accomplished by using a sequential multiple assignment randomized trial (SMART). It has been hypothesized that SMART studies may improve participant retention and generalizability.MethodsWe examine the hypotheses that SMART studies are more generalizable and have better retention than traditional randomized clinical trials via a case study of a SMART study of antipsychotic medications. We considered the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) schizophrenia study, comparing the trial participant characteristics and overall retention to those of comparable trials found via a review of all related trials conducted from 2000 onwards.ResultsA MEDLINE search returned 6435 results for primary screening; ultimately, 48 distinct trials were retained for analysis. The study population in CATIE was similar to, although perhaps less symptomatic than, the study populations of traditional randomized clinical trials (RCTs), suggesting no large gains in generalizability despite the pragmatic nature of the trial. However, CATIE did see good month-by-month retention.ConclusionsSMARTs offer the possibility of studying treatment sequences in a way that a series of traditional RCTs cannot. SMARTs may offer improved retention; however, this case study did not find evidence to suggest greater generalizability using this trial design.Trial registrationClinicalTrials.gov NCT00014001. Registered on 6 April 2001.Electronic supplementary materialThe online version of this article (doi:10.1186/s13063-016-1368-3) contains supplementary material, which is available to authorized users.

A patient and public involvement (PPI) toolkit for meaningful and flexible involvement in clinical trials - a work in progress.

Plain Language Summary Funders of research are increasingly requiring researchers to involve patients and the public in their research. Patient and public involvement (PPI) in research can potentially help researchers make sure that the design of their research is relevant, that it is participant friendly and ethically sound. Using and sharing PPI resources can benefit those involved in undertaking PPI, but existing PPI resources are not used consistently and this can lead to duplication of effort. This paper describes how we are developing a toolkit to support clinical trials teams in a clinical trials unit. The toolkit will provide a key ‘off the shelf’ resource to support trial teams with limited resources, in undertaking PPI. Key activities in further developing and maintaining the toolkit are to:● listen to the views and experience of both research teams and patient and public contributors who use the tools;● modify the tools based on our experience of using them;● identify the need for future tools;● update the toolkit based on any newly identified resources that come to light;● raise awareness of the toolkit and● work in collaboration with others to either develop or test out PPI resources in order to reduce duplication of work in PPI. Background Patient and public involvement (PPI) in research is increasingly a funder requirement due to the potential benefits in the design of relevant, participant friendly, ethically sound research. The use and sharing of resources can benefit PPI, but available resources are not consistently used leading to duplication of effort. This paper describes a developing toolkit to support clinical trials teams to undertake effective and meaningful PPI. Methods The first phase in developing the toolkit was to describe which PPI activities should be considered in the pathway of a clinical trial and at what stage these activities should take place. This pathway was informed through review of the type and timing of PPI activities within trials coordinated by the Clinical Trials Research Centre and previously described areas of potential PPI impact in trials.In the second phase, key websites around PPI and identification of resources opportunistically, e.g. in conversation with other trialists or social media, were used to identify resources. Tools were developed where gaps existed. Results A flowchart was developed describing PPI activities that should be considered in the clinical trial pathway and the point at which these activities should happen. Three toolkit domains were identified: planning PPI; supporting PPI; recording and evaluating PPI. Four main activities and corresponding tools were identified under the planning for PPI: developing a plan; identifying patient and public contributors; allocating appropriate costs; and managing expectations. In supporting PPI, tools were developed to review participant information sheets. These tools, which require a summary of potential trial participant characteristics and circumstances help to clarify requirements and expectations of PPI review. For recording and evaluating PPI, the planned PPI interventions should be monitored in terms of impact, and a tool to monitor public contributor experience is in development. Conclusions This toolkit provides a developing ‘off the shelf’ resource to support trial teams with limited resources in undertaking PPI. Key activities in further developing and maintaining the toolkit are to: listen to the views and experience of both research teams and public contributors using the tools, to identify the need for future tools, to modify tools based on experience of their use; to update the toolkit based on any newly identified resources that come to light; to raise awareness of the toolkit and to work in collaboration with others to both develop and test out PPI resources in order to reduce duplication of work in PPI.Electronic supplementary materialThe online version of this article (doi:10.1186/s40900-016-0029-8) contains supplementary material, which is available to authorized users.