Trnd Bot Free Trial

[Shameka Roessler]

Evidencebased public health decisions are based on evaluations of intervention studies with randomized and nonrandomized designs. Transparent reporting is crucial for assessing the validity and efficacy of these intervention studies, and, it facilitates synthesis of the findings for evidence-based recommendations. Therefore, the mission of the Transparent Reporting of Evaluations with Nonrandomized Designs (TREND) group is to improve the reporting standards of nonrandomized evaluations of behavioral and public health interventions.

The TREND statement [338 KB]1 has a 22-item checklist [368 KB] specifically developed to guide standardized reporting of nonrandomized controlled trials. The TREND statement complements the widely adopted CONsolidated Standards Of Reporting Trials (CONSORT) statement developed for randomized controlled trials. A collective effort in promoting transparent reporting is valuable to improve research synthesis and advance evidence-based recommendations for best practices and policies. We encourage all researchers, funding agencies, journal editors, and reviewers to use the TREND Statement as a guide when designing evaluation studies, reporting evaluation results, and reviewing manuscripts for scientific publication.

The TREND statement was first published in a special issue of the American Journal of Public Health in March 2004. The issue was devoted to evaluation research. This special issue contains a number of papers related to the use of nonrandomized or quasi-experimental designs in the evaluation of interventions.

1 Des Jarlais DC, Lyles C, Crepaz N, and the TREND Group. Improving the reporting quality of nonrandomized evaluations of behavioral and public health interventions: The TREND statement. Am J Public Health. 2004;94:361-366.

The TREND trial showed that intravenous tirofiban can reduce the risk of early neurologic deterioration (ND) following ischemic stroke without increasing the risk of bleeding. IV tirofiban reduced the risk of early ND by 68% versus oral aspirin with no difference in 90-day mortality and no severe bleeding events.

Tirofiban is widely used in coronary artery disease, Dr. Zhao noted. Multiple trials have demonstrated that tirofiban is safe and beneficial in patients with acute ischemic stroke. And because dysphagia is a common issue following stroke, an IV antiplatelet agent has clear treatment advantages over an oral agent.

This investigator-initiated study compared IV tirofiban (214 patients) versus oral aspirin (212 patients) across 10 comprehensive stroke centers in China. Patients were randomized to receive IV tirofiban or oral aspirin for 72 hours within 24 hours of onset of acute, non-cardioembolic stroke. All patients then received oral aspirin for 90 days.

Early ND occurred in 4.2% of the tirofiban group versus 13.2% of the aspirin group. None of the patients in the tirofiban group experienced intracerebral hemorrhage, and there was no significant difference in 90-day mortality, 1.3% in the tirofiban group versus 1.5% in the aspirin group.

A recent secondary analysis of the Stroke Preclinical Assessment Network (SPAN) 1.0 multicenter preclinical (animal) trial of six potential cerebroprotective interventions has confirmed the benefits of uric acid (UA) exogenous supplementation across multiple subgroups. These results reinforce both the cerebroprotective benefits of UA and the usefulness of including multiple animal models in translational stroke research.

UA is a potent endogenous scavenger of peroxynitrite and other reactive species generated in the cerebrovascular unit during and after acute cerebral ischemia. The University of Iowa proposed UA as its candidate intervention for SPAN 1.0. In addition to UA, SPAN 1.0 tested tocilizumab, veliparib, fingolimod, fasudil and remote ischemic conditioning that were proposed by five other U.S. institutions. This secondary analysis assessed only UA along with IV control.Rakeshkumar Patel, PhD

SPAN brings clinical trial design and methodology to preclinical research to reduce or eliminate the biases that can reduce scientific rigor and improve replicability of results generated in multiple laboratories. Using a randomized, placebo-controlled, blinded, multilaboratory, multistage, multi-arm approach improves the selection of stroke cerebroprotectants that have a higher likelihood of success in human clinical trials.

Animal models included young, aging and diet-induced obese mice, young rats and spontaneously hypertensive rats. All animals were randomized to receive an intravenous injection of UA 16 mg/kg or vehicle for 20 minutes, starting 5 minutes before reperfusion of a middle cerebral artery filament occlusion.

The primary outcome was the modified corner test, a standard assessment of sensorimotor dysfunction. Animals enter a corner and the direction in which they turn is recorded. Following stroke, which causes contralateral limb deficits, animals tend to use their ipsilateral limb to turn back from the corner. Animals without sensorimotor dysfunction do not show a preference for either direction when turning away from the corner.

The phase 3 Rescue on Reperfusion Damage in Cerebral Infarction by Nelonemdaz (RODIN) trial of the potential neuroprotectant nelonemdaz (nelo) administered in conjunction with thrombectomy for acute ischemic stroke failed to show benefit in functional outcomes in a population of over 400 patients. There was, however, a significant benefit for a subgroup of patients treated less than 60 minutes from arrival in the emergency department.

Nelo is a derivative of aspirin and sulfasalazine that acts as a selective NMDA receptor antagonist and potent antioxidant, Dr. Kwon said. The small molecule readily penetrates the blood-brain barrier to ameliorate NMDA receptor-mediated endotoxicity and reduce reactive oxygen species toxicity, both major pathways of brain cell death following acute ischemic stroke. Preclinical models demonstrated better safety and neuroprotection than NMDA receptor antagonists or antioxidants alone, early phase clinical trials demonstrated both safety and clear outcome trends suggesting efficacy.

The goal was to administer drug before reperfusion, but infusion was allowed up to 60 minutes after groin puncture for thrombectomy, Dr. Kwon said. The primary outcome was modified Rankin scale (mRS) at 90 days.

There was no difference in median mRS between the two groups 90 days after treatment, Dr. Kwon said, no difference in the proportion of patients with mRS 0-2, and no difference in adverse events. The only significant treatment effect was a statistically significant improvement in mRS for patients who were treated within 60 minutes of arrival in a post-hoc subgroup analysis. Another phase 3 trial of nelo is being planned for moderate-severe ischemic stroke patients who can receive the drug within 70 minutes of arrival at the emergency room and potentially before thrombectomy.

The Phase 3 GOLDEN BRIDGE-II trial compared a stroke-specific AI-CDSS that integrated multiple hospital-based clinical information systems, stroke image analysis, stroke etiology classification and guideline-based treatment recommendations to conventional hospital-based care without AI-CDSS. The objective was to compare conventional care and stroke AI-CDSS in stroke care quality and clinical outcomes in patients with acute ischemic stroke.

The study population included 21,579 patients treated in 77 hospitals across China. The population was randomized at the hospital level, with 38 institutions and 11,085 patients in the AI-CDSS intervention group versus 39 hospitals and 10,604 patients in the conventional care control group. Patients were 66-67 years old and 24% female, with a mean NIHSS score of 3 at baseline.

The primary outcomes were new vascular events, a composite of ischemic stroke, hemorrhagic stroke, myocardial infarction or vascular death, within three months of a primary ischemic stroke. Secondary outcomes included evidence-based measures of acute ischemic stroke care and disability as measured by modified Rankin Scale score at three months. Safety outcomes included bleeding events and all-cause mortality within three months.

More than 6,500 rare and neglected diseases have been identified, yet only about 250 treatments are available for these conditions. The limited numbers of patients can make gathering information and designing drug studies difficult. As a result, scientists often know little about the symptoms and biology of these conditions. Also, some private companies may find it difficult to justify the cost of developing drugs for such small rare disease markets.

The goal of the TRND program is to encourage and speed the development of new treatments for rare and neglected diseases. The program is designed to advance the entire field of therapeutic development by supporting scientific and technological innovations to improve success rates in the crucial preclinical stage of development.

TRND closes the gap that often exists between a basic research discovery and testing of new drugs in humans. That work includes the optimization and preclinical testing of therapies, with the goal to generate sufficient-quality data to support successful IND applications to the FDA and first-in-human studies in limited situations. Therapeutic clinical candidates that reach this stage should be attractive to biotechnology and pharmaceutical companies to take into clinical development.

Our pilot project is testing the feasibility of increasing the efficiency of gene therapy clinical trials by using the same gene delivery system and manufacturing methods for multiple gene therapies.

Researchers have launched a clinical trial to evaluate the drug candidate DEX-M74 as a treatment for a rare degenerative muscle disease, hereditary inclusion body myopathy (HIBM). National Institutes of Health scientists from the National Center for Advancing Translational Sciences (NCATS) and the National Human Genome Research Institute (NHGRI) will conduct the clinical trial at the NIH Clinical Center.

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