Search

The global SARS-COV-2 pandemic has significantly impacted the delivery of clinical care as well as the conduct of international clinical trials. A coordinated, multinational acupuncture study, consisting of three parallel randomized studies with a planned pooled analysis of individual patient data, was initiated in 2019 with the goal of assessing whether acupuncture relieved hot flash symptoms in hormone receptor-positive breast cancer patients prescribed adjuvant endocrine therapy. Eligibility included persistent hot flashes on endocrine therapy. Participants were randomly assigned to receive either immediate or delayed acupuncture in equal proportions; the primary endpoint was assessed at week 10, after completion of the immediate acupuncture treatments and before the delayed treatment sessions began. The trial was conducted in China, South Korea and United States of America (USA) and was in the midst of enrollment and study procedures when the COVID-19 pandemic began. Despite numerous challenges, the study was nonetheless completed successfully. We deployed a process evaluation method to describe each site’s experiences in conducting this multinational study during the pandemic. Using these observations, we offer measures for the planning and conduct of future studies, taking into account preparedness considerations in the event of exigent and demanding global circumstances.

IMPORTANCE: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease of the motor nervous system. Clinical studies have demonstrated cortical and spinal motor neuron hyperexcitability using transcranial magnetic stimulation and threshold tracking nerve conduction studies, respectively, although metrics of excitability have not been used as pharmacodynamic biomarkers in multi-site clinical trials. OBJECTIVE: To ascertain whether ezogabine decreases cortical and spinal motor neuron excitability in ALS. DESIGN, SETTING, AND PARTICIPANTS: This double-blind, placebo-controlled phase 2 randomized clinical trial sought consent from eligible participants from November 3, 2015, to November 9, 2017, and was conducted at 12 US sites within the Northeast ALS Consortium. Participants were randomized in equal numbers to a higher or lower dose of ezogabine or to an identical matched placebo, and they completed in-person visits at screening, baseline, week 6, and week 8 for clinical assessment and neurophysiological measurements. INTERVENTIONS: Participants were randomized to receive 600 mg/d or 900 mg/d of ezogabine or a matched placebo for 10 weeks. MAIN OUTCOMES AND MEASURES: The primary outcome was change in short-interval intracortical inhibition (SICI; SICI(−1) was used in analysis to reflect stronger inhibition from an increase in amplitude) from pretreatment mean at screening and baseline to the full-dose treatment mean at weeks 6 and 8. The secondary outcomes included levels of cortical motor neuron excitability (including resting motor threshold) measured by transcranial magnetic stimulation and spinal motor neuron excitability (including strength-duration time constant) measured by threshold tracking nerve conduction studies. RESULTS: A total of 65 participants were randomized to placebo (23), 600 mg/d of ezogabine (23), and 900 mg/d of ezogabine (19 participants); 45 were men (69.2%) and the mean (SD) age was 58.3 (8.8) years. The SICI(−1) increased by 53% (mean ratio, 1.53; 95% CI, 1.12-2.09; P = .009) in the 900-mg/d ezogabine group vs placebo group. The SICI(−1) did not change in the 600-mg/d ezogabine group vs placebo group (mean ratio, 1.15; 95% CI, 0.87-1.52; P = .31). The resting motor threshold increased in the 600-mg/d ezogabine group vs placebo group (mean ratio, 4.61; 95% CI, 0.21-9.01; P = .04) but not in the 900-mg/d ezogabine group vs placebo group (mean ratio, 1.95; 95% CI, −2.64 to 6.54; P = .40). Ezogabine caused a dose-dependent decrease in excitability by several other metrics, including strength-duration time constant in the 900-mg/d ezogabine group vs placebo group (mean ratio, 0.73; 95% CI, 0.60 to 0.87; P

IntroductionResearch coordinators (RCs) are vital to the clinical research enterprise, ensuring research is conducted ethically, results are scientifically sound and human research subjects are protected. Given the absence of a prior systematic inquiry, we sought to understand the ways in which Clinical & Translational Science Award-funded academic health centers support RCs.MethodsOur survey asked questions about existing coordinator networks and where none existed, collected data on the characterization of resources and services provided to support RCs (outside of salary).ResultsFindings show 4 mechanisms support RCs: identification of the workforce, professionalization of the position, dissemination of information, and offering of services.ConclusionAn academic health center that wishes to deliver research training and services to their RC workforce will need identification and communication structures in place before supportive activities can be effectively implemented.

Background Although research participation is essential for clinical investigation, few quantitative outcome measures exist to assess participants’ experiences. To address this, we developed and deployed a survey at 15 NIH-supported clinical research centers to assess participant-centered outcomes; we report responses from 4,961 participants. Methods Survey questions addressed core aspects of the research participants’ experience, including their overall rating, motivation, trust, and informed consent. We describe participant characteristics, responses to individual questions, and correlations among responses. Results Respondents broadly represented the research population in sex, race, and ethnicity. Seventy-three percent awarded top ratings to their overall research experience and 94% reported no pressure to enroll. Top ratings correlated with feeling treated with respect, listened to, and having access to the research team (R2 = 0.80–0.96). White participants trusted researchers more (88%) than did nonwhite participants collectively (80%; p < 0.0001). Many participants felt fully prepared by the informed consent process (67%) and wanted to receive research results (72%). Conclusions Our survey demonstrates that a majority of participants at NIH-supported clinical research centers rate their research experience very positively and that participant-centered outcome measures identify actionable items for improvement of participant's experiences, research protections, and the conduct of clinical investigation.

Intracerebral hemorrhage (ICH) is the stroke subtype with the worst prognosis and has no established acute treatment. ICH is classified as lobar or nonlobar based on the location of ruptured blood vessels within the brain. These different locations also signal different underlying vascular pathologies. Heritability estimates indicate a substantial genetic contribution to risk of ICH in both locations. We report a genome-wide association study of this condition that meta-analyzed data from six studies that enrolled individuals of European ancestry. Case subjects were ascertained by neurologists blinded to genotype data and classified as lobar or nonlobar based on brain computed tomography. ICH-free control subjects were sampled from ambulatory clinics or random digit dialing. Replication of signals identified in the discovery cohort with p < 1 × 10(-6) was pursued in an independent multiethnic sample utilizing both direct and genome-wide genotyping. The discovery phase included a case cohort of 1,545 individuals (664 lobar and 881 nonlobar cases) and a control cohort of 1,481 individuals and identified two susceptibility loci: for lobar ICH, chromosomal region 12q21.1 (rs11179580, odds ratio [OR] = 1.56, p = 7.0 × 10(-8)); and for nonlobar ICH, chromosomal region 1q22 (rs2984613, OR = 1.44, p = 1.6 × 10(-8)). The replication included a case cohort of 1,681 individuals (484 lobar and 1,194 nonlobar cases) and a control cohort of 2,261 individuals and corroborated the association for 1q22 (p = 6.5 × 10(-4); meta-analysis p = 2.2 × 10(-10)) but not for 12q21.1 (p = 0.55; meta-analysis p = 2.6 × 10(-5)). These results demonstrate biological heterogeneity across ICH subtypes and highlight the importance of ascertaining ICH cases accordingly.

The revolution in human genetics, catalyzed by the sequencing of the human genome in 2003 and the development of genome-wide genotyping technologies, has led to the identification of >2000 trait-associated genetic variants. Because most of these variants have individually small effects on disease risk, successful gene discovery efforts have required large sample sizes (involving thousands, tens, or hundreds of thousands of cases and controls) to achieve sufficient study power. Amassing such sample sizes has depended on international collaboration on a scale never seen before in human genetics or even in clinical research. Disease-specific consortia bringing together many individual sites and collaborators have now evolved for many major diseases. Each consortium has faced with ≥2 fundamental questions: how to assemble a study sample of sufficient size, homogeneity, and phenotypic quality and how to retain and analyze, sometimes repeatedly over several years, biological samples from enrolled subjects. The International Stroke Genetics Consortium (ISGC) has addressed these 2 challenges by taking into account the nature of the disease—stroke occurs suddenly with high case fatality (≤251 per 100 000; 5.9 million of 53 million reported deaths in 2010)1,2 and develops through multiple biological mechanisms. Because the stroke community consists of clinicians and investigators from across the world practicing in a range of environments with varied resources and constraints, the ISGC has developed processes that allow maximum flexibility while maintaining standardization, reliability, and quality. A central tenet of the consortium involves transparency and trust, without which large-scale collections and studies would not be possible. The growing collection of stroke samples created at the Massachusetts General Hospital under the auspices of the ISGC includes physical samples for ≈5000 cases and 4500 controls from >20 institutions in Europe, North America, South America, Australia, and Asia. …

Background and Purpose— Previous studies suggest that genetic variation plays a substantial role in occurrence and evolution of intracerebral hemorrhage (ICH). Genetic contribution to disease can be determined by calculating heritability using family-based data, but such an approach is impractical for ICH because of lack of large pedigree-based studies. However, a novel analytic tool based on genome-wide data allows heritability estimation from unrelated subjects. We sought to apply this method to provide heritability estimates for ICH risk, severity, and outcome. Methods— We analyzed genome-wide genotype data for 791 ICH cases and 876 controls, and determined heritability as the proportion of variation in phenotype attributable to captured genetic variants. Contribution to heritability was separately estimated for the APOE (encoding apolipoprotein E) gene, an established genetic risk factor, and for the rest of the genome. Analyzed phenotypes included ICH risk, admission hematoma volume, and 90-day mortality. Results— ICH risk heritability was estimated at 29% (SE, 11%) for non- APOE loci and at 15% (SE, 10%) for APOE . Heritability for 90-day ICH mortality was 41% for non- APOE loci and 10% (SE, 9%) for APOE . Genetic influence on hematoma volume was also substantial: admission volume heritability was estimated at 60% (SE, 70%) for non- APOE loci and at 12% (SE, 4%) for APOE . Conclusions— Genetic variation plays a substantial role in ICH risk, outcome, and hematoma volume. Previously reported risk variants account for only a portion of inherited genetic influence on ICH pathophysiology, pointing to additional loci yet to be identified.