Opportunities and counterintuitive challenges for decentralized clinical trials to broaden participant inclusion.

Traditional clinical trials have often failed to recruit representative participant populations. Just 5% of eligible patients participate in clinical research. Participants, particularly those from minority groups, cite geographical constraints, mistrust, miscommunication, and discrimination as barriers. Here, an intersectional view of inclusion in clinical trials provides significant insights into the complex and counterintuitive challenges of trial design and participant recruitment. The US FDA have recently proposed that decentralized clinical trials (DCTs) might reduce barriers and appeal to a wider range of participants by reducing the costs and commitments required for patients to participate. While common sense and early evidence suggests that allowing participants to take part in trials at or near home has advantages in terms of convenience, travel, and perhaps even infection control, it remains to be seen if DCT approaches will yield significant improvements on participant inclusivity. Some digital studies aiming to be more inclusive on a single element of inclusion, such as race, have experienced unintended consequences in other elements, like education or gender. Implementing DCTs presents new challenges including the digital divide, the exclusion of certain tests and procedures, complexities of at-home medication delivery, and the need to build new infrastructure. We present a range of challenges and opportunities for researchers to adopt and adapt DCT approaches to create reliable evidence that applies to all of us.

Assessing the impact of insurance type on COVID-19 mortality in black and white patients in the largest healthcare system in the state of georgia.

IMPORTANCE: The increased COVID-19 mortality for Black individuals over White individuals may be explained by the known racial disparities in access to insurance. OBJECTIVE: To determine whether racial disparities in COVID-19 mortality still exist when Blacks and Whites are equally insured. DESIGN: Routinely collected data on race, mortality, type of insurance, known risk factors, and lab results from the EPIC Patient Management System were analyzed using a multivariable logistic regression model. SETTING: Piedmont Healthcare is the largest hospital system in Georgia. Due to its multiple locations across the state of Georgia, it receives a relatively equitably insured population. PARTICIPANTS: All patients hospitalized with a positive COVID-19 status between March 1 and November 30, 2020. MAIN OUTCOMES: We hypothesized that Black patients would not have higher odds of mortality than White patients, and that type of insurance would predict COVID-19 mortality. RESULTS: 6,881 (3,674 Black, 3,207 White; 48% male, mean age = 60) patients were included. Race was not a significant predictor of COVID-19 mortality (p>0.05). When controlling for age and insurance, the mortality rate for Black patients was not statistically significant from that for White patients (p>0.05). Compared to those relying on Medicare, patients with commercial (OR=0.68, 95% CI: 0.48-0.96) or out-of-pocket (self-pay) insurance (OR=0.22, 95% CI: 0.03-0.88) had lower odds of mortality. CONCLUSIONS: National trends of racial disparities in COVID-19 mortality may be partially explained by disparities in insurance.

Pre-existing cardiovascular disease, acute kidney injury, and cardiovascular outcomes in hospitalized blacks with COVID-19 infection.

BACKGROUND: The Corona Virus 19 (COVID-19) infection is associated with worse outcomes in blacks, although the mechanisms are unclear. We sought to determine the significance of black race, pre-existing cardiovascular disease (pCVD), and acute kidney injury (AKI) on cardiopulmonary outcomes and in-hospital mortality of COVID-19 patients. METHODS: We conducted a retrospective cohort study of blacks with/without pCVD and with/without in-hospital AKI, hospitalized within Grady Memorial Hospital in Georgia between February and July 2020, who tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on qualitative polymerase-chain-reaction assay. The primary outcome was a composite of in-hospital cardiac events. RESULTS: Of the 293 patients hospitalized with COVID-19 in this study, 71 were excluded from the primary analysis (for race/ethnicity other than black non-Hispanic). Of the 222 hospitalized COVID-19 patients included in our analyses, 41.4% were female, 78.8% had pCVD, and 30.6% developed AKI during the admission. In multivariable analyses, pCVD (OR 4.7, 95% CI 1.5-14.8, P=0.008) and AKI (OR 2.7, 95% CI 1.3-5.5, P=0.006) were associated with increased odds of in-hospital cardiac events. AKI was associated with increased odds of in-hospital mortality (OR 8.9, 95% CI 3.3-23.9, P<0.0001). The presence of AKI was associated with increased odds of ICU stay, mechanical ventilation, and acute respiratory distress syndrome (ARDS). CONCLUSION: pCVD and AKI were associated with higher risk of in-hospital cardiac events, and AKI was associated with a higher risk of in-hospital mortality in blacks.

Procedural, clinical, and health status outcomes in chronic total coronary occlusion revascularization: Results from the PERSPECTIVE study.

BACKGROUND: Limited research has detailed the outcomes of chronic total occlusion (CTO) percutaneous coronary intervention (PCI) with independent core laboratory and event adjudication. This study examined procedural, clinical, and patient-reported health status outcomes among patients undergoing CTO PCI with specific focus on outcomes for those treated with zotarolimus-eluting stents (ZES). METHODS: Among 500 consecutive patients undergoing attempted CTO PCI, procedural and in-hospital clinical outcomes were examined in addition to the 1-year composite endpoint of death, myocardial infarction, and target lesion revascularization (major adverse cardiac events, MACE). In a pre-specified cohort of 250 patients, health status measures were ascertained at baseline and 1 year. A powered secondary endpoint was 1-year MACE among patients treated with ZES compared with a performance goal. RESULTS: Demographic, lesion, and procedural characteristics for the overall population included prior bypass surgery, 29.8%; diabetes, 35.2%; occlusion length >20 mm, 71.3%; J-CTO score, 2.5 ± 1.1; and primary retrograde strategy, 30.8%. Overall guidewire crossing was 90.9%; clinical success following guidewire crossing, 94.3%; and 1-year MACE rate, 12.1%. One-year health status significantly improved from baseline with successful CTO-PCI (angina frequency, 72.7 ± 26.5 at baseline to 96.0 ± 10.8, p < .0001). Compared with a performance goal derived from prior CTO DES trials (1-year hierarchal MACE, 25.2%), treatment with ZES was associated with significantly lower MACE (18.2%, one-sided upper CI, 23.6%, p = .017). CONCLUSIONS: Favorable procedural success, health status improvements and late-term clinical outcomes inform the relative risks and benefits of CTO PCI when performed in a clinically indicated, complex patient population representative of those treated in clinical practice.

Infliximab versus ciclosporin for steroid-resistant acute severe ulcerative colitis (CONSTRUCT): a mixed methods, open-label, pragmatic randomised trial.

BACKGROUND: Infliximab and ciclosporin are of similar efficacy in treating acute severe ulcerative colitis, but there has been no comparative evaluation of their relative clinical effectiveness and cost-effectiveness. METHODS: In this mixed methods, open-label, pragmatic randomised trial, we recruited consenting patients aged 18 years or older at 52 district general and teaching hospitals in England, Scotland, and Wales who had been admitted, unscheduled, with severe ulcerative colitis and failed to respond to intravenous hydrocortisone within about 5 days. Patients were randomly allocated (1:1) to receive either infliximab (5 mg/kg intravenous infusion given over 2 h at baseline, and again at 2 weeks and 6 weeks after the first infusion) or ciclosporin (2 mg/kg per day by continuous infusion for up to 7 days, followed by twice-daily tablets delivering 5·5 mg/kg per day for 12 weeks). Randomisation used a web-based password-protected site, with a dynamic algorithm to generate allocations on request, thus protecting against investigator preference or other subversion, while ensuring that each trial group was balanced by centre, which was the only stratification used. Local investigators and participants were aware of the treatment allocated, but the chief investigator and analysts were masked. Analysis was by treatment allocated. The primary outcome was quality-adjusted survival-ie, the area under the curve (AUC) of scores from the Crohn's and Ulcerative Colitis Questionnaire (CUCQ) completed by participants at baseline, 3 months, and 6 months, then every 6 months from 1 year to 3 years. This trial is registered with the ISRCTN Registry, number ISRCTN22663589. FINDINGS: Between June 17, 2010, and Feb 26, 2013, 270 patients were recruited. 135 patients were allocated to the infliximab group and 135 to the ciclosporin group. 121 (90%) patients in each group were included in the analysis of the primary outcome. There was no significant difference between groups in quality-adjusted survival (mean AUC 564·0 [SD 241·9] in the infliximab group vs 587·0 [226·2] in the ciclosporin group; mean adjusted difference 7·9 [95% CI -22·0 to 37·8]; p=0·603). Likewise, there were no significant differences between groups in the secondary outcomes of CUCQ scores, EQ-5D, or SF-6D scores; frequency of colectomy (55 [41%] of 135 patients in the infliximab group vs 65 [48%] of 135 patients in the ciclosporin group; p=0·223); or mean time to colectomy (811 [95% CI 707-912] days in the infliximab group vs 744 [638-850] days in the ciclosporin group; p=0·251). There were no differences in serious adverse reactions (16 reactions in 14 participants receiving infliximab vs ten in nine patients receiving ciclosporin); serious adverse events (21 in 16 patients vs 25 in 17 patients); or deaths (three in the infliximab group vs none in the ciclosporin group). INTERPRETATION: There was no significant difference between ciclosporin and infliximab in clinical effectiveness. FUNDING: NIHR Health Technology Assessment programme.

Comparison Of iNfliximab and ciclosporin in STeroid Resistant Ulcerative Colitis: pragmatic randomised Trial and economic evaluation (CONSTRUCT).

BACKGROUND: The efficacy of infliximab and ciclosporin in treating severe ulcerative colitis (UC) is proven, but there has been no comparative evaluation of effectiveness. OBJECTIVE: To compare the clinical effectiveness and cost-effectiveness of infliximab and ciclosporin in treating steroid-resistant acute severe UC. METHOD: Between May 2010 and February 2013 we recruited 270 participants from 52 hospitals in England, Scotland and Wales to an open-label parallel-group, pragmatic randomised trial. Consented patients admitted with severe colitis completed baseline quality-of-life questionnaires before receiving intravenous hydrocortisone. If they failed to respond within about 5 days, and met other inclusion criteria, we invited them to participate and used a web-based adaptive randomisation algorithm to allocate them in equal proportions between 5 mg/kg of intravenous infliximab at 0, 2 and 6 weeks or 2 mg/kg/day of intravenous ciclosporin for 7 days followed by 5.5 mg/kg/day of oral ciclosporin until 12 weeks from randomisation. Further treatment was at the discretion of physicians responsible for clinical management. The primary outcome was quality-adjusted survival (QAS): the area under the curve (AUC) of scores derived from Crohn's and Ulcerative Colitis Questionnaires completed by participants at 3 and 6 months, and then 6-monthly over 1-3 years, more frequently after surgery. Secondary outcomes collected simultaneously included European Quality of Life-5 Dimensions (EQ-5D) scores and NHS resource use to estimate cost-effectiveness. Blinding was possible only for data analysts. We interviewed 20 trial participants and 23 participating professionals. Funded data collection finished in March 2014. Most participants consented to complete annual questionnaires and for us to analyse their routinely collected health data over 10 years. RESULTS: The 135 participants in each group were well matched at baseline. In 121 participants analysed in each group, we found no significant difference between infliximab and ciclosporin in QAS [mean difference in AUC/day 0.0297 favouring ciclosporin, 95% confidence interval (CI) -0.0088 to 0.0682; p = 0.129]; EQ-5D scores (quality-adjusted life-year mean difference 0.021 favouring ciclosporin, 95% CI -0.032 to 0.096; p = 0.350); Short Form questionnaire-6 Dimensions scores (mean difference 0.0051 favouring ciclosporin, 95% CI -0.0250 to 0.0353; p = 0.737). There was no statistically significant difference in colectomy rates [odds ratio (OR) 1.350 favouring infliximab, 95% CI 0.832 to 2.188; p = 0.223]; numbers of serious adverse reactions (event ratio = 0.938 favouring ciclosporin, 95% CI 0.590 to 1.493; p = 0.788); participants with serious adverse reactions (OR 0.660 favouring ciclosporin, 95% CI 0.282 to 1.546; p = 0.338); numbers of serious adverse events (event ratio 1.075 favouring infliximab, 95% CI 0.603 to 1.917; p = 0.807); participants with serious adverse events (OR 0.999 favouring infliximab, 95% CI 0.473 to 2.114; p = 0.998); deaths (all three who died received infliximab; p = 0.247) or concomitant use of immunosuppressants. The lower cost of ciclosporin led to lower total NHS costs (mean difference -£5632, 95% CI -£8305 to -£2773; p < 0.001). Interviews highlighted the debilitating effect of UC; participants were more positive about infliximab than ciclosporin. Professionals reported advantages and disadvantages with both drugs, but nurses disliked the intravenous ciclosporin. CONCLUSIONS: Total cost to the NHS was considerably higher for infliximab than ciclosporin. Nevertheless, there was no significant difference between the two drugs in clinical effectiveness, colectomy rates, incidence of SAEs or reactions, or mortality, when measured 1-3 years post treatment. To assess long-term outcome participants will be followed up for 10 years post randomisation, using questionnaires and routinely collected data. Further studies will be needed to evaluate the efficacy and effectiveness of new anti-tumour necrosis factor drugs and formulations of ciclosporin. TRIAL REGISTRATION: Current Controlled Trials ISRCTN22663589. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 20, No. 44. See the NIHR Journals Library website for further project information.

Randomised controlled trial. Comparison Of iNfliximab and ciclosporin in STeroid Resistant Ulcerative Colitis: Trial design and protocol (CONSTRUCT).

INTRODUCTION: Many patients with ulcerative colitis (UC) present with acute exacerbations needing hospital admission. Treatment includes intravenous steroids but up to 40% of patients do not respond and require emergency colectomy. Mortality following emergency colectomy has fallen, but 10% of patients still die within 3 months of surgery. Infliximab and ciclosporin, both immunosuppressive drugs, offer hope for treating steroid-resistant UC as there is evidence of their short-term effectiveness. As there is little long-term evidence, this pragmatic randomised trial, known as Comparison Of iNfliximab and ciclosporin in STeroid Resistant Ulcerative Colitis: a Trial (CONSTRUCT), aims to compare the clinical and cost-effectiveness of infliximab and ciclosporin for steroid-resistant UC. METHODS AND ANALYSIS: Between May 2010 and February 2013, 52 UK centres recruited 270 patients admitted with acute severe UC who failed to respond to intravenous steroids but did not need surgery. We allocated them at random in equal proportions between infliximab and ciclosporin.The primary clinical outcome measure is quality-adjusted survival, that is survival weighted by Crohn's and Colitis Questionnaire (CCQ) participants' scores, analysed by Cox regression. Secondary outcome measures include: the CCQ-an extension of the validated but community-focused UK Inflammatory Bowel Disease Questionnaire (IBDQ) to include patients with acute severe colitis and stoma; two general quality of life measures-EQ-5D and SF-12; mortality; survival weighted by EQ-5D; emergency and planned colectomies; readmissions; incidence of adverse events including malignancies, serious infections and renal disorders; disease activity; National Health Service (NHS) costs and patient-borne costs. Interviews investigate participants' views on therapies for acute severe UC and healthcare professionals' views on the two drugs and their administration. ETHICS AND DISSEMINATION: The Research Ethics Committee for Wales has given ethical approval (Ref. 08/MRE09/42); each participating Trust or Health Board has given NHS Reseach & Development approval. We plan to present trial findings at international and national conferences and publish in high-impact peer-reviewed journals. TRIAL REGISTRATION NUMBER ISRCTN: 22663589; EudraCT number: 2008-001968-36.