Meeting the challenges of retention and enrollment of study participants in clinical trials during the COVID-19 pandemic from the study leadership perspective: Experience from the Zoster Eye Disease Study (ZEDS).

PURPOSE: To describe steps taken that enabled a high rate of retention and early resumption of enrollment in the Zoster Eye Disease Study (ZEDS), a randomized controlled trial funded by the National Eye Institute, during the first 13 months (3/1/2020-3/31/2021) of the COVID-19 pandemic. METHODS: A number of responses were implemented in ZEDS when the focus shifted to retention of study participants at the beginning of the pandemic including frequent communication with the participating clinical centers (PCCs) about remote visits, local lab work, shipping study medication, and completion of revised case report forms. Additional payments were provided to the PCCs. Remote activation of PCCs continued. Screening and enrollment visits gradually resumed when allowed. RESULTS: Communication with PCCs increased, and average attendance at monthly coordinator teleconferences went up from 17 to 47. Remote visits peaked in April 2020, accounting for 75% (33/44) of study visits, then declined to less than 10% of study visits beginning August 2020. Overall, 97% (590/609) of study visits were completed. Only 5.5% (9/165) of study participants withdrew consent, and 2.4% (4/165) were lost to follow-up. Enrollment returned to pre-pandemic levels by September 2020. DISCUSSION: Strong communication and unwavering commitment, combined with the technological capability for remote work, visits, and shipment of study medication, were key to the successful retention of study participants and resumption of enrollment. CONCLUSIONS: Rapid responses to challenges to trials caused by the COVID-19 pandemic can enable them to continue successfully and provide insights into the planning of future trials.

Anesthetic type and risk of myocardial infarction after carotid endarterectomy in the Carotid Revascularization Endarterectomy versus Stenting Trial (CREST).

OBJECTIVE: Carotid endarterectomy (CEA) is usually performed under general anesthesia (GA), although some advocate regional anesthesia (RA) to reduce hemodynamic instability and allow neurologic monitoring and selective shunting. RA does not reduce risk of periprocedural stroke or death, although some series show a reduction in myocardial infarction (MI). We investigated the association of anesthesia type and periprocedural MI among patients receiving GA or RA for CEA and patients undergoing carotid artery stenting (CAS) in the Carotid Revascularization Endarterectomy versus Stenting Trial (CREST). METHODS: Between 2000 and 2008, 1151 patients underwent CEA (anesthetic type available for 1149 patients), and 1123 patients underwent CAS ≤30 days of randomization in CREST. CEA patients were categorized by anesthetic type (GA vs RA). CREST defined protocol MI as chest pain or electrocardiogram change plus biomarker evidence of MI, and total MI was defined as protocol MI plus biomarker-positive (+)-only MI. The incidence of protocol MI and total MI in patients undergoing CEA under GA and RA were compared with those undergoing CAS. Other study end points were similarly compared. Differences in baseline characteristics and periprocedural events were evaluated among the three groups. Logistic regression, adjusting for age and symptomatic status, was used to assess group differences. RESULTS: The three groups had similar demographic risk factors, except for prevalence of symptomatic carotid stenosis, which was lowest in the CEA-RA group (P = .03). Of the 111 patients in the CEA-RA group, no protocol MIs occurred and only two biomarker+-only MIs, for an overall incidence of 1.8%, similar to the 1.7% overall incidence in patients undergoing CAS. In contrast, the combined incidence of protocol and biomarker+-only MIs in the 1038 patients in the CEA-GA group was significantly higher at 3.4% (P = .04), twice the risk of protocol MI and biomarker+-only MI compared with those undergoing CAS (odds ratio [OR], 2.01; 95% confidence interval [CI], 1.14-3.54). Direct comparison of the MI incidence between CEA-RA and CEA-GA showed no statistical difference. Patients undergoing CEA-GA had lower odds of a periprocedural stroke (OR, 0.48; 95% CI, 0.28-0.79) and stroke or death (OR, 0.46; 95% CI, 0.27-0.76) compared with those undergoing CAS but were not significantly different from those undergoing CEA-RA. CONCLUSIONS: Patients in CREST undergoing CEA-RA had a similar risk of periprocedural MI as those undergoing CAS, whereas the risk for CEA-GA was twice that compared with patients undergoing CAS. Nevertheless, because periprocedural MI is one of the few variables favoring CAS over CEA and has been associated with decreased long-term survival, RA should be seriously considered for patients undergoing CEA.

Characteristics of participants consenting versus declining follow-up for up to 10 years in a randomized clinical trial.

BACKGROUND: With patients living a decade or longer post-procedure, long-term data are needed to assess the durability of carotid artery stenting versus carotid endarterectomy. Identifying characteristics of those consenting or declining to continue in long-term follow-up may suggest strategies to improve retention in clinical trials. PURPOSE: This report describes differences between patients choosing or declining to continue follow-up for up to 10 years in the Carotid Revascularization Endarterectomy versus Stenting Trial. METHODS: Following completion of the primary outcome, patients who were in active Carotid Revascularization Endarterectomy versus Stenting Trial follow-up were asked to continue beyond their original 4-year commitment for a maximum of 10 years. The characteristics of those who consented were compared with those who declined. Univariate and multivariable logistic regression were used for analysis, and backwards stepwise logistic regression (the most parsimonious model) was used to determine the factors associated with continuation. RESULTS: Of the 1921 active Carotid Revascularization Endarterectomy versus Stenting Trial participants for whom consent to extend follow-up was requested, 1695 (88%; mean age: 68.4) consented; 226 (12%; mean age: 69.6) declined. Of those who did not consent versus those who consented, 66% versus 48% were symptomatic at baseline (p<0.0001), at follow-up 28% versus 20% were smokers (p=0.009), 85% versus 90% were hypertensive (p=0.01), and 84% versus 94% were dyslipidemic (p<0.0001). Additional factors that differed between those who did not consent and those who consented included the mean number of years in the study at time of consent (4.8 years vs 3.7 years (p=<0.0001)) and patients from sites that enrolled <30 patients compared to sites randomizing 30 or more (70% vs 52% (p<0.0001)). Multivariable logistic regression indicated that those with lesser odds of consenting to the extended follow-up were older (odds ratio: 0.80; 95% confidence interval: 0.67, 0.96), more likely to be symptomatic (odds ratio: 0.58; 95% confidence interval: 0.42, 0.80), smokers (odds ratio: 0.48; 95% confidence interval: 0.34, 0.70), were in the study 5+ years versus <3 (odds ratio: 0.21; 95% confidence interval: 0.13, 0.34), and at a site that randomized <30 patients (odds ratio: 0.46; 95% confidence interval: 0.33, 0.63), while patients with dyslipidemia at follow-up had increased odds of consenting (odds ratio: 2.28 (1.47, 3.54)). CONCLUSION: Symptomatic status, increasing age, randomized at lower volume centers, and longer time in follow-up were associated with reduced odds of consenting to long-term follow-up. Identifying factors associated with reduced willingness to extend participation long-term can suggest targeted strategies to improve retention in future clinical trials.

Incidence, outcomes, and effect on quality of life of cranial nerve injury in the Carotid Revascularization Endarterectomy versus Stenting Trial.

OBJECTIVE: Cranial nerve injury (CNI) is the most common neurologic complication of carotid endarterectomy (CEA) and can cause significant chronic disability. Data from prior randomized trials are limited and provide no health-related quality of life (HRQOL) outcomes specific to CNI. Incidence of CNIs and their outcomes for patients in the Carotid Revascularization Endarterectomy vs Stenting Trial (CREST) were examined to identify factors predictive of CNI and their impact on HRQOL. METHODS: Incidence of CNIs, baseline and procedural characteristics, outcomes, and HRQOL scores were evaluated in the 1151 patients randomized to CEA and undergoing surgery ≤30 days. Patients with CNI were identified and classified using case report forms, adverse event data, and clinical notes. Baseline and procedural characteristics were compared using descriptive statistics. Clinical outcomes at 1 and 12 months were analyzed. All data were adjudicated by two neurologists and a vascular surgeon. HRQOL was evaluated using the Medical Outcomes Short-Form 36 (SF-36) Health Survey to assess general health and Likert scales for disease-specific outcomes at 2 weeks, 4 weeks, and 12 months after CEA. The effect of CNI on SF-36 subscales was evaluated using random effects growth curve models, and Likert scale data were compared by ordinal logistic regression. RESULTS: CNI was identified in 53 patients (4.6%). Cranial nerves injured were VII (30.2%), XII (24.5%), and IX/X (41.5%), and 3.8% had Horner syndrome. CNI occurred in 52 of 1040 patients (5.0%) receiving general anesthesia and in one of 111 patients (0.9%) operated on under local anesthesia (P = .05). No other predictive baseline or procedural factors were identified. Deficits resolved in 18 patients (34%) at 1 month and in 42 of 52 patients (80.8%) by 1 year. One patient died before the 1-year follow-up visit. The HRQOL evaluation showed no statistical difference between groups with and without CNI at any interval. By Likert scale analysis, the group with CNI showed a significant difference in the difficulty eating/swallowing parameter at 2 and 4 weeks (P < .001) but not at 1 year. CONCLUSIONS: In CREST, CNI occurred in 4.6% of patients undergoing CEA, with 34% resolution at 30 days and 80.8% at 1 year. The incidence of CNI was significantly higher in patients undergoing general anesthesia. CNI had a small and transient effect on HRQOL, negatively affecting only difficulty eating/swallowing at 2 and 4 weeks but not at 1 year. On the basis of these findings, we conclude that CNI is not a trivial consequence of CEA but rarely results in significant long-term disability.

Complication rates and center enrollment volume in the carotid revascularization endarterectomy versus stenting trial.

BACKGROUND AND PURPOSE: Evidence indicates that center volume of cases affects outcomes for both carotid endarterectomy and stenting. We evaluated the effect of enrollment volume by site on complication rates in the Carotid Revascularization Endarterectomy Versus Stenting Trial (CREST). METHODS: The primary composite end point was any stroke, myocardial infarction, or death within 30 days or ipsilateral stroke in follow-up. The 477 approved surgeons performed >12 procedures per year with complication rates <3% for asymptomatic patients and <5% for symptomatic patients; 224 interventionists were certified after a rigorous 2 step credentialing process. CREST centers were divided into tertiles based on the number of patients enrolled into the study, with Group 1 sites enrolling <25 patients, Group 2 sites enrolling 25 to 51 patients, and Group 3 sites enrolling >51 patients. Differences in periprocedural event rates for the primary composite end point and its components were compared using logistic regression adjusting for age, sex, and symptomatic status within site-volume level. RESULTS: The safety of carotid angioplasty and stenting and carotid endarterectomy did not vary by site-volume during the periprocedural period as indicated by occurrence of the primary end point (P=0.54) or by stroke and death (P=0.87). A trend toward an inverse relationship between center enrollment volume and complications was mitigated by adjustment for known risk factors. CONCLUSIONS: Complication rates were low in CREST and were not associated with center enrollment volume. The data are consistent with the value of rigorous training and credentialing in trials evaluating endovascular devices and surgical procedures. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT00004732.

Financial management of a large multisite randomized clinical trial.

BACKGROUND: The Carotid Revascularization Endarterectomy versus Stenting Trial (CREST) received five years' funding ($21 112 866) from the National Institutes of Health to compare carotid stenting to surgery for stroke prevention in 2500 randomized participants at 40 sites. AIMS: Herein we evaluate the change in the CREST budget from a fixed to variable-cost model and recommend strategies for the financial management of large-scale clinical trials. METHODS: Projections of the original grant's fixed-cost model were compared to the actual costs of the revised variable-cost model. The original grant's fixed-cost budget included salaries, fringe benefits, and other direct and indirect costs. For the variable-cost model, the costs were actual payments to the clinical sites and core centers based upon actual trial enrollment. We compared annual direct and indirect costs and per-patient cost for both the fixed and variable models. Differences between clinical site and core center expenditures were also calculated. RESULTS: Using a variable-cost budget for clinical sites, funding was extended by no-cost extension from five to eight years. Randomizing sites tripled from 34 to 109. Of the 2500 targeted sample size, 138 (5·5%) were randomized during the first five years and 1387 (55·5%) during the no-cost extension. The actual per-patient costs of the variable model were 9% ($13 845) of the projected per-patient costs ($152 992) of the fixed model. CONCLUSIONS: Performance-based budgets conserve funding, promote compliance, and allow for additional sites at modest additional cost. Costs of large-scale clinical trials can thus be reduced through effective management without compromising scientific integrity.

Interventions to increase enrollment in a large multicenter phase 3 trial of carotid stenting vs. endarterectomy.

BACKGROUND: Randomized clinical trials often encounter slow enrollment. Failing to meet sample size requirements has scientific, financial, and ethical implications. AIMS: We report interventions used to accelerate recruitment in a large multicenter clinical trial that was not meeting prespecified enrollment commitments. METHODS: The Carotid Revascularization Endarterectomy vs. Stenting Trial began randomization in December 2000. To accelerate enrollment, multiple recruitment tactics were initiated, which included expanding the number of sites, hiring a recruitment director (May 2003), broadening eligibility criteria (April 2005), branding with a study logo, Web site, and recruitment materials, increasing site visits by study leadership, sending e-mails to the site teams after every enrollment, distributing electronic newsletters, and implementing investigator and coordinator conferences. RESULTS: From December 2000 through May 2003, 14 sites became active (54 patients randomized), from June 2003 through April 2005, 44 sites were added (404 patients randomized), and from May 2005 through July 2008, 54 sites were added (2044 patients randomized). During these time intervals, the number of patients enrolled per site per year was 1·5, 3·6, and 5·6. For the single years 2004 to 2008, the mean monthly randomization rates per year were 19·7, 38·1, 56·4, 53·0, and 54·7 (annualized), respectively. Enrollment was highest after recruitment tactics were implemented: 677 patients in 2006, 636 in 2007, and 657 in 2008 (annualized). The prespecified sample size of 2502 patients, 47% asymptomatic, was accomplished on July 2008. CONCLUSIONS: Aggressive recruitment tactics and investment in a full-time recruitment director who can lead implementation may be effective in accelerating recruitment in multicenter trials.

The Carotid Revascularization Endarterectomy versus Stenting Trial: credentialing of interventionalists and final results of lead-in phase.

The success of carotid artery stenting in preventing stroke requires a low risk of periprocedural stroke and death. A comprehensive training and credentialing process was prerequisite to the randomized Carotid Revascularization Endarterectomy versus Stenting Trial (CREST) to assemble a competent team of interventionalists with low periprocedural event rates. Interventionalists submitted cases to a multidisciplinary Interventional Management Committee. This committee evaluated 427 applicants. Of these, 238 (56%) were selected to participate in the training program and the lead-in phase, 73 (17%) who had clinical registry experience and satisfactory results with the devices used in CREST were exempt from training and were approved for the randomized phase, and 116 (27%) did not qualify for training. At 30 days in the lead-in study, stroke, myocardial infarction, or death occurred in 6.1% of symptomatic subjects and 4.8% of asymptomatic subjects. Stroke or death occurred in 5.8% of symptomatic subjects and 3.8% of asymptomatic subjects. Outcomes were better for younger subjects and varied by operator training. Based on experience, training, and lead-in results, the Interventional Management Committee selected 224 interventionalists to participate in the randomized phase of CREST. We believe that the credentialing and training of interventionalists participating in CREST have been the most rigorous reported to date for any randomized trial evaluating endovascular treatments. The study identified competent operators, which ensured that the randomized trial results fairly contrasted outcomes between endarterectomy and stenting.

Does sex matter? Thirty-day stroke and death rates after carotid artery stenting in women versus men: results from the Carotid Revascularization Endarterectomy versus Stenting Trial (CREST) lead-in phase.

BACKGROUND AND PURPOSE: Several carotid endarterectomy randomized, controlled trials and series have reported higher perioperative stroke and death rates for women compared with men. The potential for this same relationship with carotid artery stenting was examined in the lead-in phase of the Carotid Revascularization Endarterectomy versus Stenting Trial (CREST). METHODS: CREST compares efficacy of carotid endarterectomy and carotid artery stenting in preventing stroke, myocardial infarction, and death in the periprocedural period and ipsilateral stroke over the follow-up period. CREST included a "lead-in" phase of symptomatic (>or=50% stenosis) and asymptomatic (>or=70% stenosis) patients. Patients were examined by a neurologist preprocedure, at 24 hours, and at 30 days. Review of stroke and death was by an independent events committee. The association of sex with periprocedural stroke and death was examined in 1564 patients undergoing carotid artery stenting (26.5% symptomatic). RESULTS: Women comprised 37% of the lead-in cohort and did not differ from men by age, symptomatic status, or characteristics of the internal carotid artery. The 30-day stroke and death rate for women was 4.5% (26 of 579; 95% CI, 3.0% to 6.5%) compared with 4.2% (41 of 985; 95% CI, 3.0% to 5.6%) for men. The difference in stroke and death rate was not significant nor were there any significant differences by sex after adjustment for age, arterial characteristics, or cardiovascular risk factors. CONCLUSIONS: These results do not provide evidence that women have a higher carotid artery stenting stroke and death rate compared with men. The potential differential periprocedural risk by sex will be prospectively addressed in the randomized phase of CREST.

Quantitative electroencephalographic studies of cue-induced cocaine craving.

Quantitative electroencephalographic (qEEG) profiles were studied in cocaine dependent patients in response to cocaine cue exposure. Using neurometric analytical methods, the spectral power of each primary bandwidth was computed and topographically mapped. Additional measures of cue-reactivity included cocaine craving, anxiety and related subjective ratings, and physiological measures of skin conductance, skin temperature, heart rate, and plasma cortisol and HVA levels. Twenty-four crack cocaine-dependent subjects were tested for their response to tactile, visual and audio cues related to crack cocaine or neutral items. All measures were analyzed for significant difference by comparing cocaine versus neutral cue conditions. An increase in cocaine craving, anxiety and related subjective ratings, elevated plasma cortisol levels, and a decrease in skin temperature, were induced by cocaine cue exposure. Distinct qEEG profiles were found during the paraphernalia handling and video viewing (eyes-open), and guided imagery (eyes-closed), phases of cocaine cue exposure. During paraphernalia handling and video viewing, there was an increase in beta activity accompanied by a drop in delta power in the frontal cortex, and an increase in beta mean frequency in the occipital cortex. In contrast, during guided imagery there was an increase in theta and delta power in the frontal cortex, and an increase in beta power in the occipital cortex. Correlation analyses revealed that cue-induced anxiety during paraphernalia handling and video viewing was associated with reduced high frequency and enhanced low frequency EEG activity. These findings demonstrated that EEG activation during cue-induced cocaine craving may be topographically mapped and subsequently analyzed for functional relevance.