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1.
Approaches to Disease Modification for Parkinson's Disease: Clinical Trials and Lessons Learned.
Hung, AY, Schwarzschild, MA
Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics. 2020;(4):1393-1405
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Abstract
Despite many clinical trials over the last three decades, the goal of demonstrating that a treatment slows the progression of Parkinson's disease (PD) remains elusive. Research advances have shed new insight into cellular pathways contributing to PD pathogenesis and offer increasingly compelling therapeutic targets. Here we review recent and ongoing clinical trials employing novel strategies toward disease modification, including those targeting alpha-synuclein and those repurposing drugs approved for other indications. Active and passive immunotherapy approaches are being studied with the goal to modify the spread of alpha-synuclein pathology in the brain. Classes of currently available drugs that have been proposed to have potential disease-modifying effects for PD include calcium channel blockers, antioxidants, anti-inflammatory agents, iron-chelating agents, glucagon-like peptide 1 agonists, and cAbl tyrosine kinase inhibitors. The mechanistic diversity of these treatments offers hope, but to date, results from these trials have been disappointing. Nevertheless, they provide useful lessons in guiding future therapeutic development.
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Heart Failure End Points in Cardiovascular Outcome Trials of Sodium Glucose Cotransporter 2 Inhibitors in Patients With Type 2 Diabetes Mellitus: A Critical Evaluation of Clinical and Regulatory Issues.
Butler, J, Packer, M, Greene, SJ, Fiuzat, M, Anker, SD, Anstrom, KJ, Carson, PE, Cooper, LB, Fonarow, GC, Hernandez, AF, et al
Circulation. 2019;(25):2108-2118
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Abstract
Following regulatory guidance set forth in 2008 by the US Food and Drug Administration for new drugs for type 2 diabetes mellitus, many large randomized, controlled trials have been conducted with the primary goal of assessing the safety of antihyperglycemic medications on the primary end point of major adverse cardiovascular events, defined as cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. Heart failure (HF) was not specifically mentioned in the US Food and Drug Administration guidance and therefore it was not a focus of these studies when planned. Several trials subsequently showed the impact of antihyperglycemic drugs on HF outcomes, which were not originally specified as the primary end point of the trials. The most impressive finding has been the substantial and consistent risk reduction in HF hospitalization seen across 4 trials of sodium glucose cotransporter 2 inhibitors. However, to date, these results have not led to regulatory approval of any of these drugs for a HF indication or a recommendation for use by US HF guidelines. It is therefore important to explore to what extent persuasive treatment effects on nonprimary end points can be used to support regulatory claims and guideline recommendations. This topic was discussed by researchers, clinicians, industry sponsors, regulators, and representatives from professional societies, who convened on the US Food and Drug Administration campus on March 6, 2019. This report summarizes these discussions and the key takeaway messages from this meeting.
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Physics aspects of setting up a multicenter clinical trial involving internal dosimetry of radioiodine treatment of differentiated thyroid cancer.
Taprogge, J, Leek, F, Flux, GD
The quarterly journal of nuclear medicine and molecular imaging : official publication of the Italian Association of Nuclear Medicine (AIMN) [and] the International Association of Radiopharmacology (IAR), [and] Section of the Society of.... 2019;(3):271-277
Abstract
The field of molecular radiotherapy is expanding rapidly, with the advent of many new radiotherapeutics for the treatment of common as well as for rare cancers. Treatment outcome is dependent on the absorbed doses delivered to target volumes and to healthy organs-at-risk, which are shown to vary widely from fixed administrations of activity. There have been significant developments in quantitative imaging and internal dosimetry in recent years, although clinical implementation of these methods has been slow in comparison with external beam radiotherapy, partly due to there being relatively few patients treated at single centers. Multicenter clinical trials are therefore essential to acquire the data required to ensure best practice and to develop the personalized treatment planning that this area is well suited to, due to the unrivalled opportunity to image the therapeutic drug in vivo. Initial preparation for such trials requires a significant effort in terms of resources and trial design. Imaging systems in participating centers must be characterized and set up for quantitative imaging to allow for collation of data. Data transfer for centralized processing is usually necessary but is hindered in some cases by data protection regulations and local logistics. Recent multicenter clinical trials involving radioiodine therapy have begun to establish the procedures necessary for quantitative SPECT imaging in a multicenter setting using standard and anthropomorphic phantoms. The establishment of national and international multicenter imaging and dosimetry networks will provide frameworks to develop and harmonize best practice with existing therapeutic procedures and to ensure rapid and optimized clinical implementation of new radiotherapeutics across all centers of excellence that offer molecular radiotherapy. This will promote networks and collaborations that can provide a sound basis for further developments and will ensure that nuclear medicine maintains a key role in future developments.
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Evaluating Whole Grain Intervention Study Designs and Reporting Practices Using Evidence Mapping Methodology.
Sawicki, CM, Livingston, KA, Ross, AB, Jacques, PF, Koecher, K, McKeown, NM
Nutrients. 2018;(8)
Abstract
Consumption of whole grains have been associated with reduced risk of chronic diseases in many observational studies; yet, results of intervention studies are mixed. We aimed to use evidence mapping to capture the methodological and reporting variability in whole grain intervention studies that may contribute to this inconsistency. We conducted a reproducible search in OVID Medline for whole grain human intervention studies (published 1946 to February 2018). After screening based on a priori criteria, we identified 202 publications describing a total of 213 unique trials. Over half (55%) were acute trials, lasting ≤1 day, 30% were moderate duration studies (up to 6 weeks) and 15% were of longer duration (more than 6 weeks). The majority of acute trials (75%) examined measures of glycaemia and/or insulinemia, while most of the longer trials included measures of cardiometabolic health (71%), appetite/satiety (57%) and weight/adiposity (56%). Among the moderate and long duration trials, there was a wide range of how whole grains were described but only 10 publications referenced an established definition. Only 55% of trials reported the actual amount of whole grains (in grams or servings), while 36% reported the amount of food/product and 9% did not report a dose at all. Of the interventions that provided a mixture of whole grains, less than half (46%) reported the distribution of the different grain types. Reporting of subject compliance also varied and only 22% used independent biomarkers of whole grain intake. This evidence map highlights the need to standardize both study protocols and reporting practices to support effective synthesis of study results and provide a stronger foundation to better inform nutrition scientists and public health policy.
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Primary Prevention of CVD: The Role of Imaging Trials.
Rozanski, A, Muhlestein, JB, Berman, DS
JACC. Cardiovascular imaging. 2017;(3):304-317
Abstract
The optimal approach for screening for cardiovascular disease remains controversial. A new standard of "therapeutic efficacy" requires that screening tests which involve cardiac imaging not only predict events but also improve clinical outcomes compared with usual care. To date, 5 prospective randomized trials have been conducted to compare outcomes based on imaging-guided screening and prevention versus assignment to usual care in screening populations. One trial involved cardiac stress imaging, 3 involved coronary artery calcium scanning, and 1 involved coronary computed tomography angiography. Due to the current very low event risk in asymptomatic populations, these trials have been substantially underpowered to assess the impact of imaging-guided prevention on hard cardiac events. This review derives lessons learned from these trials relative to the future design of imaging-based screening trials, including analysis regarding the optimal methods for screening, and what are the relevant clinical outcomes to assess the efficacy of imaging-based screening for prevention.
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Updates on cardiovascular outcome trials in diabetes.
Schnell, O, Rydén, L, Standl, E, Ceriello, A, ,
Cardiovascular diabetology. 2017;(1):128
Abstract
In 2008 the Food and Drug Administration introduced a guidance for industry that requires the investigation of cardiovascular outcomes of glucose-lowering medications. Since then, an increasing number of cardiovascular outcome trials have been completed in diabetes patients with high cardiovascular risk for members of the SGLT-2 and DPP4 inhibitors and GLP-1 receptor agonist classes. The trials confirmed cardiovascular safety for all tested anti-hyperglycaemic drugs and, in addition empagliflozin, semaglutide and liraglutide could even reduce cardiovascular risk. The present review summarizes the results of the DEVOTE, CANVAS, EXSCEL and ACE trials that tested cardiovascular safety of Insulin degludec, canagliflozin, once-weekly exenatide and acarbose and were published in 2017. We provide context on these results by comparing them with earlier trials of glucose-lowering drugs and give an outlook on what to expect in coming years.
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Full-Endoscopic Procedures Versus Traditional Discectomy Surgery for Discectomy: A Systematic Review and Meta-analysis of Current Global Clinical Trials.
Li, XC, Zhong, CF, Deng, GB, Liang, RW, Huang, CM
Pain physician. 2016;(3):103-18
Abstract
BACKGROUND Traditional discectomy surgery (TDS) provides good or excellent results in clinical surgical discectomy but may induce neural adhesion, spinal structural damage, instability, and other complications. The potential advantages of full-endoscopic (FE) procedures over standard TDS include less blood loss, less postoperative pain, shorter hospitalization, and an earlier return to work. However, more evidence is needed to support this new technology in clinical applications. OBJECTIVE The aim of this systematic review and meta-analysis was to compare the safety and efficacy of FE and TDS. STUDY DESIGN Comprehensive systematic review and meta-analysis of the literature. METHODS Electronic databases, including PubMed, EMBASE, SinoMed, and Cochrane Library, were searched to identify clinical therapeutic trials comparing FE to TDS for discectomy. RESULTS Six trials comprising 730 patients were included, and the overall quality of the literature was moderate, including 4 Grade I levels of evidence (4 randomized controlled trials, [RCTs]) and 2 Grade II levels (2 non-RCTs). The pooled data revealed no difference in reoperation rates between FE and TDS (P = 0.94), but the complication rate was significantly lower in the FE group (3.86%) than in the TDS group (11.4%). Perioperative parameters (operation time, blood loss, hospitalization time, and return to work days) were significantly lower in the FE group (P < 0.05 for all groups using either score). Postoperative pain and neurology score assessments were conducted at 4 different time points at 3 months, 6 months, 12 months, and 24 months. Significant differences were detected in the following: lumbar North American Spine Society (NASS) pain at 6 months (P = 0.008); cervical NASS neurology at 6 months (P = 0.03); visual analog scale (VAS) score in leg at 3 months (P < 0.001); VAS score in arm at 24 months (P = 0.002); VAS score in neck at 3 months, 6 months, and 12 months after therapy (P = 0.003, P = 0.004, P = 0.01); and VAS score in neck at 3 months and 6 months (P = 0.01, P = 0.004). Moreover, the pooled data revealed no statistically significant differences in improvements in the Oswestry disability index (ODI), instability (X-ray), and Hilibrand criteria (P > 0.05 for all groups). LIMITATIONS Only 6 studies were included, 4 of which had the same authors. Between-study heterogeneity due to differences in socioeconomic factors, nutrition, and matching criteria is difficult to avoid. CONCLUSIONS Based on this meta-analysis of 24 months of clinical results, we conclude that the FE procedure is as effective as TDS but has the additional benefits of lower complication rates and superior perioperative parameters. In addition, patients may experience less pain with FE techniques due to a smaller incision and less operative injury. However, large-volume, well-designed RCTs with extensive follow-up are needed to confirm and update the findings of this analysis.
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Clinical trials of new drugs for the treatment of rheumatoid arthritis: focus on early disease.
Smolen, JS, Collaud Basset, S, Boers, M, Breedveld, F, Edwards, CJ, Kvien, TK, Miossec, P, Sokka-Isler, T, van Vollenhoven, RF, Abadie, EC, et al
Annals of the rheumatic diseases. 2016;(7):1268-71
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Abstract
The European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases convened a task force of experts in rheumatoid arthritis (RA) and clinical trial methodology to comment on the new draft 'Guideline on clinical investigation of medicinal products for the treatment of RA' released by the European Medicines Agency (EMA). Special emphasis was placed by the group on the development of new drugs for the treatment of early RA. In the absence of a clear definition of early RA, it was suggested that clinical investigations in this condition were conducted in disease-modifying antirheumatic drugs naïve patients with no more than 1 year disease duration. The expert group recommended using an appropriate improvement in disease activity (American College of Rheumatology (ACR) or Simplified/Clinical Disease Activity Index (SDAI/CDAI) response criteria) or low disease activity (by any score) as primary endpoints, with ACR/European League Against Rheumatism remission as a secondary endpoint. Finally, as compelling evidence showed that the Disease Acrivity Score using 28-joint counts (DAS28) might not provide a reliable definition of remission, or sometimes even low disease activity, the group suggested replacing DAS28 as a measurement instrument to evaluate disease activity in RA clinical trials. Proposed alternatives included SDAI, CDAI and Boolean criteria.
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The Case For and Against a Coronary Artery Calcium Trial: Means, Motive, and Opportunity.
McEvoy, JW, Martin, SS, Blaha, MJ, Polonsky, TS, Nasir, K, Kaul, S, Greenland, P, Blumenthal, RS
JACC. Cardiovascular imaging. 2016;(8):994-1002
Abstract
Numerous observational studies have shown that coronary artery calcium (CAC) imaging can improve cardiovascular risk assessment in asymptomatic adults. Whether CAC imaging can improve cardiovascular outcomes as part of an overall risk reduction strategy compared to alternative care approaches has not been demonstrated in clinical trials. Therefore, the role of CAC imaging in primary prevention of cardiovascular disease is somewhat contentious. Advocates for expanded CAC testing offer the large amount of observational data as support for their position, while opponents to wider CAC testing propose that only a clinical trial can resolve the matter. This paper reviews the arguments for and against such a trial based on clinical, safety and economic considerations. We also propose potential trial approaches based on recent changes in clinical practice that could make a new CAC trial design feasible.
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Report From the NEI/FDA Diabetic Retinopathy Clinical Trial Design and Endpoints Workshop.
Nair, P, Aiello, LP, Gardner, TW, Jampol, LM, Ferris, FL
Investigative ophthalmology & visual science. 2016;(13):5127-5142