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Clinically, the principles of extinction learning form much of the foundation for the most effective behavioral therapies for fear-related anxiety disorders. Within the general class of anxiety disorders, posttraumatic stress disorder (PTSD) is unique in the sense that the precipitating traumatic event may provide the opportunity for acute intervention before the onset of symptoms and before memories have been consolidated. The use of propranolol to treat individuals with posttraumatic stress symptoms was initially described in a case series of physically and sexually abused children with severe symptoms of agitation. An alternative consolidation-blockade approach to the use of propranolol involves the administration of glucocorticoids to trauma-exposed patients. Finally, clinically directed interference with initial memory consolidation through the use of beta-blockers or glucocorticoids following acute trauma exposure could prevent or attenuate the formation of traumatic emotional memory and reduce risk of PTSD.
Special trial designs have been developed to distinguish the symptomatic and disease modifying effects of treatment using clinical outcome measures. These designs, termed 'two-period' designs, include the so-called withdrawal and delayed-start (or 'staggered-start') designs and their variations. This chapter describes these study designs in terms of their rationale, assumptions, design features, implementation, statistical analysis, and sample size considerations. It also discusses the important limitations of the designs. Simulation studies using disease progression modeling suggest that the withdrawal design may provide more power than the delayed start design to detect disease-modifying effects of a treatment. A statistical model for data from a complete two-period design assumes that a normally-distributed outcome termed µ 2. There are alternative approaches to evaluating the disease-modifying effects of an intervention that require only a single treatment period.
This book comprehensively reviews the current state of clinical trial methods in multiple sclerosis treatment, providing investigators, sponsors and specialists with current knowledge of outcome measures and study designs for disease and symptom management. The status of the rapidly evolving field of disease-modifying drugs is presented, with emphasis on the most promising therapies currently being tested. Experts discuss disease and symptom management for MS subtypes, including neuromyelitis optica and pediatric MS. In addition, key scientific advances in MS pathology, genetics, immunology and epidemiology are presented. The fourth edition has been extensively revised, featuring more than 50% new material. All chapters have been substantially updated to provide current information on rapidly evolving topics and this volume contains 15 new chapters, reflecting the growth of the field in recent years. This book is an essential reference for practitioners caring for MS patients, investigators planning or conducting clinical trials, and clinical trial sponsors.
Multiple sclerosis (MS) research in recent years has identified an increasing number of potential therapeutic products that can be evaluated. The ultimate goal of a drug development program is to establish that the drug has a favorable effect upon the patient and has risks that are acceptable in light of the benefit. The Kurtzke Expanded Disability Status Scale (EDSS) is employed as the chief physical disability measure in development programs for many of the currently available therapies. An important aspect of drug development is determining what drug benefits should be claimed in the approved drug labeling. Biomarkers have the potential to be informative on a number of different aspects of biological responses in much shorter time and fewer patients, and contribute to feasible and successful drug development. An important aspect of efficient and informative drug development programs is selection of appropriate end-points for each study in the clinical development program.
The emergence of optical coherence tomography (OCT) technologies has allowed measurements of retinal nerve fiber layer (RNFL) and macular thickness that complement the history and clinical examination in distinguishing forms of acute optic neuropathy and retinal disease. High-resolution Fourier domain OCT has allowed for rapid imaging of the retina as well as three-dimensional imaging and improved volumetric measurements. Ongoing studies of OCT in clinical trials and research examine patterns of axonal degeneration and visual loss over time, and establish the role for OCT and other ocular imaging modalities as structural markers. With the emergence of a variety of OCT techniques, including Fourier Domain OCT, future studies will also help establish the protocols for data analysis to provide meaningful information about changes in structure from baseline. OCT is likely to play an increasing role in multiple sclerosis (MS) trials for measuring both axonal integrity and neuronal preservation.
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