Health Screening Program to Enhance Enrollment of Women and Minorities in CREST-2

Background and Purpose: The CREST-2 (Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis Trial) consists of 2 parallel randomized stroke prevention trials in patients with asymptomatic high-grade stenosis of the cervical carotid artery. The purpose of this report is to detail the outcomes of a health screening effort to increase trial enrollment of women and minorities. Methods: Life Line screening (LLS) conducts nationwide screening for vascular disease. Screenings within a 50-mile radius of each CREST-2 center were identified for participation in a joint CREST-LLS program over the course of one year (November 2018 to October 2019) whereby patients with an abnormal carotid ultrasound were referred to the local CREST-2 center for further workup, management, and potential consideration for trial enrollment. Results: LLS completed the screening of 588 198 individuals in 29 732 zip codes across the United States. Of those, 230 021 individuals were screened at events occurring near a CREST-2 clinical center and 646 (0.3%) were found to have abnormal carotid ultrasound findings. Each of the 646 individuals was contacted by CREST-LLS program staff for permission to be referred to their local CREST-2 center; 200 (31%) consented to be contacted by CREST-2. Of those, 39 (19.5%) agreed to be, and were, evaluated at their local CREST-2 center. High-grade stenosis was confirmed in 27 patients. A total of 3 patients were eligible for the trial and were enrolled, one woman but no racial/ethnic minorities. Conclusions: The LLS program appears to identify community-living individuals with high-grade carotid stenosis through ultrasonography. However, the prevalence of abnormal carotid findings was low. In addition, screening and offering participation into the CREST-2 trial had no substantial impact on the proportion of women and minorities enrolled in the trial. Additional innovative strategies are needed to promote enrollment of diverse patients with carotid stenosis into stroke prevention trials.

On the Move or Barely Moving? Age-Related Changes in Physical Activity, Sedentary, and Sleep Behaviors by Weekday/Weekend Following Pandemic Control Policies

This study examined pre-pandemic (2017-early March 2020) to early-pandemic (Spring 2020) changes in moderate-to-vigorous PA (MVPA), light PA (LPA), and sedentary behavior/sleep (SS), by weekday/weekend, and age (preschool, elementary, middle school). We re-enrolled children from two pre-pandemic obesity prevention trials and examined differences in accelerometer-measured PA from pre-pandemic to early-pandemic across age groups using linear mixed models. Children (n = 75) were 51% multiple race/ethnicities, 29% preschool, 28% elementary, 43% middle school, 65% suburban, 21% rural, and 13% urban. Pre-pandemic to early-pandemic changes in weekday MVPA (p = 0.006), LPA (p = 0.018), and SS (p = 0.003) differed by age. On weekdays, middle schoolers’ MVPA decreased 15.36 min/day (p = 0.002) and SS increased 94.36 min/day (p < 0.001) with non-significant changes among preschoolers and elementary schoolers. Compared to elementary schoolers, middle schoolers’ changes in weekday MVPA (b = −16.34, p = 0.036) and SS (b = 63.28, p = 0.039) significantly differed. Declines in weekday MVPA and increases in SS among middle schoolers suggest that, compared with younger children, middle schoolers are dependent on school and recreational facilities for PA, and in their absence engage in more sedentary activities and sleep.

Meeting report: South African Medical Research Council Standard of Care in Clinical Research in Low- And Middle-Income Settings Summit, November 2017

A cornerstone of HIV prevention clinical trials is providing a combination prevention package to all trial participants. The elements included in that standard of care (SoC) package evolve as new prevention modalities are developed. Pre-exposure prophylaxis (PrEP) was recommended by the World Health Organization for persons at high risk of acquiring HIV, but not all countries immediately adopted those recommendations. The South African Medical Research Council (SAMRC) convened a summit to discuss issues relating to SoC and PrEP in HIV prevention clinical trials taking place in lower- to middle-income countries (LMIC). Policymakers, regulators, ethicists, experts in law, researchers, representatives of advocacy groups, and the HIV Vaccine Trials Network (HVTN) presented a framework within which SoC principles could be articulated. A group of subject matter experts presented on the regulatory, ethical, scientific, and historic framework of SoC in clinical trials, focusing on PrEP in South Africa. Summit participants discussed how and when to include new HIV treatment and prevention practices into existing clinical guidelines and trial protocols, as well as the opportunities for and challenges to scaling up interventions. The summit addressed challenges to PrEP provision, such as inconsistent efficacy amongst different populations and various biological, virological, and immunological explanations for this heterogeneity. Advocates and community members propagated the urgent need for accessible interventions that could avert HIV infection. The meeting recommended supporting access to PrEP in HIV prevention trials by (1) developing PrEP access plans for HIV vaccine trials, (2) creating a PrEP fund that would supply PrEP to sites conducting HIV prevention trials via a central procurement mechanism, and (3) supporting the safety monitoring of PrEP. This report summarizes the presentations and discussions from the summit in order to highlight the importance of SoC in HIV prevention clinical trials.

P.034 Eptinezumab Demonstrated Early Relief from Episodic and Chronic Migraine: Consistency of Effect Across 4 Clinical Trials

Background: Eptinezumab is approved in the US for migraine prevention. We demonstrate the consistency in migraine reduction from Day 1 across 4 weeks in patients with episodic (EM) or chronic migraine (CM) treated with eptinezumab. Methods: Four double-blind, placebo-controlled, randomized trials evaluated eptinezumab for migraine prevention: NCT01772524 (EM); NCT02559895 (EM, PROMISE-1); NCT02275117 (CM); NCT02974153 (CM, PROMISE-2). The percentage of patients experiencing migraine was evaluated on Day 1, then as an averaged daily occurrence weekly through Wk4; baseline was averaged over the 28-day screening period. Results: Approximately 31% of EM patients experienced migraine on any given day during baseline. PROMISE-1 percentages of patients with migraine on Day 1: 14.8% (100mg), 13.9% (300mg), 22.5% (placebo); during Wk4: 17.1%, 15.8%, 20.5%. NCT01772524 on Day 1: 4.8% (1000mg), 13.7% (placebo); during Wk4: 10.0%, 17.6%. Approximately 58-59% of CM patients experienced migraine on any given day during baseline. PROMISE-2 percentages on Day 1: 28.6% (100mg), 27.8% (300mg), 42.3% (placebo); during Wk4: 31.8%, 28.8%, 36.0%. NCT02275117 on Day 1: 29.3% (100mg), 26.5% (300mg), 48.7% (placebo); during Wk4: 30.2%, 30.1%, 41.0%. Conclusions: Across 4 migraine prevention trials, eptinezumab consistently demonstrated rapid onset of migraine preventive benefit, beginning Day 1 after initial treatment and sustained through ≥4 weeks.

Statistical reanalysis of vascular event outcomes in primary and secondary vascular prevention trials

Background Vascular prevention trials typically use dichotomous event outcomes although this may be inefficient statistically and gives no indication of event severity. We assessed whether ordinal outcomes would be more efficient and how to best analyse them. Methods Chief investigators of vascular prevention randomised controlled trials that showed evidence of either benefit or harm, or were included in a systematic review that overall showed benefit or harm, shared individual participant data from their trials. Ordered categorical versions of vascular event outcomes (such as stroke and myocardial infarction) were analysed using 15 statistical techniques and their results then ranked, with the result with the smallest p-value given the smallest rank. Friedman and Duncan’s multiple range tests were performed to assess differences between tests by comparing the average ranks for each statistical test. Results Data from 35 trials (254,223 participants) were shared with the collaboration. 13 trials had more than two treatment arms, resulting in 59 comparisons. Analysis approaches (Mann Whitney U, ordinal logistic regression, multiple regression, bootstrapping) that used ordinal outcome data had a smaller average rank and therefore appeared to be more efficient statistically than those that analysed the original binary outcomes. Conclusions Ordinal vascular outcome measures appear to be more efficient statistically than binary outcomes and provide information on the severity of event. We suggest a potential role for using ordinal outcomes in vascular prevention trials.

Multidomain interventions: state-of-the-art and future directions for protocols to implement precision dementia risk reduction. A user manual for Brain Health Services—part 4 of 6

Although prevention of dementia and late-life cognitive decline is a major public health priority, there are currently no generally established prevention strategies or operational models for implementing such strategies into practice. This article is a narrative review of available evidence from multidomain dementia prevention trials targeting several risk factors and disease mechanisms simultaneously, in individuals without dementia at baseline. Based on the findings, we formulate recommendations for implementing precision risk reduction strategies into new services called Brain Health Services. A literature search was conducted using medical databases (MEDLINE via PubMed and SCOPUS) to select relevant studies: non-pharmacological multidomain interventions (i.e., combining two or more intervention domains), target population including individuals without dementia, and primary outcomes including cognitive/functional performance changes and/or incident cognitive impairment or dementia. Further literature searches covered the following topics: sub-group analyses assessing potential modifiers for the intervention effect on cognition in the multidomain prevention trials, dementia risk scores used as surrogate outcomes in multidomain prevention trials, dementia risk scores in relation to brain pathology markers, and cardiovascular risk scores in relation to dementia. Multidomain intervention studies conducted so far appear to have mixed results and substantial variability in target populations, format and intensity of interventions, choice of control conditions, and outcome measures. Most trials were conducted in high-income countries. The differences in design between the larger, longer-term trials that met vs. did not meet their primary outcomes suggest that multidomain intervention effectiveness may be dependent on a precision prevention approach, i.e., successfully identifying the at-risk groups who are most likely to benefit. One such successful trial has already developed an operational model for implementing the intervention into practice. Evidence on the efficacy of risk reduction interventions is promising, but not yet conclusive. More long-term multidomain randomized controlled trials are needed to fill the current evidence gaps, especially concerning low- and middle-income countries and integration of dementia prevention with existing cerebrovascular prevention programs. A precision risk reduction approach may be most effective for dementia prevention. Such an approach could be implemented in Brain Health Services.

Challenges in recruiting children to a multidrug-resistant TB prevention trial

BACKGROUND: Recruitment to randomised clinical trials can be challenging and slow recruitment has serious consequences. This study aimed to summarise and reflect on the challenges in enrolling young children to a multidrug-resistant TB (MDR-TB) prevention trial in South Africa.METHODS: Recruitment to the Tuberculosis Child Multidrug-resistant Preventive Therapy Trial (TB-CHAMP) was tracked using an electronic recruiting platform, which was used to generate a recruiting flow diagram. Structured personnel questionnaires, meeting minutes and workshop notes were thematically analysed to elucidate barriers and solutions.RESULT: Of 3,682 (85.3%) adult rifampicin (RIF) resistant index cases with pre-screening outcomes, 1597 (43.4%) reported having no children under 5 years in the household and 562 (15.3%) were RIF-monoresistant. More than nine index cases were pre-screened for each child enrolled. Numerous barriers to recruitment were identified. Thorough recruitment planning, customised tracking data systems, a dedicated recruiting team with strong leadership, adequate resources to recruit across large geographic areas, and excellent relationships with routine TB services emerged as key factors to ensure successful recruitment.CONCLUSION: Recruitment of children into MDR-TB prevention trials can be difficult. Several MDR-TB prevention trials are underway, and lessons learnt from TB-CHAMP will be relevant to these and other TB prevention studies.