Open-Label Surgical Trials for Parkinson Disease: Time for Reconsideration

Department of Neurosurgery, Mount Sinai School of Medicine, New York, NY, USA.
Annals of Neurology (Impact Factor: 9.98). 07/2011; 70(1):5-8. DOI: 10.1002/ana.22453
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Available from: Michele Tagliati, Oct 05, 2015
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    • "While definitions for " clinical proof-of-concept " vary among published studies, the vast majority of published accounts with which we are familiar include evidence of clear clinical benefit often (but not always) involving a randomized, controlled clinical design. The latter requirement seems particularly important for CNS indications and essential for surgical-based therapies (e.g., see arguments raised by Alterman et al., 2011), including PD. Moreover, given the subjective nature of most of the validated measures used to assess severity of PD symptoms, it also seems important that improvement be seen on a number of different , clinically relevant, motor and health-related, quality-oflife assessments that provide a greater level of confidence via mutually corroborating evidence. "
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    ABSTRACT: Neurotrophic factors have long shown promise as potential therapies for age-related neurodegenerative diseases. However, 20 years of largely disappointing clinical results have underscored the difficulties involved with safely and effectively delivering these proteins to targeted sites within the central nervous system. Recent progress establishes that gene transfer can now likely overcome the delivery issues plaguing the translation of neurotrophic factors. This may be best exemplified by adeno-associated virus serotype-2-neurturin (CERE-120), a viral-vector construct designed to deliver the neurotrophic factor, neurturin to degenerating nigrostriatal neurons in Parkinson's disease. Eighty Parkinson's subjects have been dosed with CERE-120 (some 7+ years ago), with long-term, targeted neurturin expression confirmed and no serious safety issues identified. A double-blind, controlled Phase 2a trial established clinical "proof-of-concept" via 19 of the 24 prescribed efficacy end points favoring CERE-120 at the 12-month protocol-prescribed time point and all but one favoring CERE-120 at the 18-month secondary time point (p = 0.007 and 0.001, respectively). Moreover, clinically meaningful benefit was seen with CERE-120 on several specific protocol-prescribed, pairwise, blinded, motor, and quality-of-life end points at 12 months, and an even greater number of end points at 18 months. Because the trial failed to meet the primary end point (Unified Parkinson's Disease Rating Scale motor-off, measured at 12 months), a revised multicenter Phase 1/2b protocol was designed to enhance the neurotrophic effects of CERE-120, using insight gained from the Phase 2a trial. This review summarizes the development of CERE-120 from its inception through establishing "clinical proof-of-concept" and beyond. The translational obstacles and issues confronted, and the strategies applied, are reviewed. This information should be informative to investigators interested in translational research and development for age-related and other neurodegenerative diseases.
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    ABSTRACT: There have been several recent scientific advances in gene-based and cell-based therapies that might translate into novel therapeutic approaches for neurodegenerative disorders. Such therapies might need to be directly delivered into the CNS, and complex scientific and ethical assessment will be needed to determine whether a sham neurosurgical arm should be included in clinical trials assessing these agents. We have developed a framework of points for investigators to consider when designing trials that involve direct delivery of a therapeutic agent to the CNS. The inclusion of a sham neurosurgical arm will be guided in part by the objectives of the clinical study (preliminary safety, optimisation, and feasibility vs preliminary efficacy vs confirmatory efficacy) and the need to minimise bias and confounds. Throughout the clinical development process, the perspectives of researchers, ethicists, and patients must be considered, and risks should be minimised whenever possible in a manner that is consistent with good trial design.
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    ABSTRACT: Deep brain stimulation (DBS) surgery has become increasingly utilized in the treatment of advanced Parkinson's disease. Over the past decade, a number of studies have demonstrated that DBS is superior to best medical management in appropriately selected patients. The primary targets for DBS in Parkinson's disease include the subthalamic nucleus and the internal segment of the globus pallidus, both of which improve the cardinal motor features in Parkinson's disease. Recent randomized studies have revealed that both targets are similarly effective in treating the motor symptoms of Parkinson's disease, but emerging evidence suggests that the globus pallidus may be the preferred target in many patients, based on differences in nonmotor outcomes. Here, we review appropriate patient selection, and the efficacy and safety of DBS therapy in Parkinson's disease. Best outcomes are achieved if the problems of the individual patient are considered when evaluating surgical candidates and considering whether the subthalamic nucleus or the globus pallidus internus should be targeted.
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