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1.
Christopher G Goetz Kimberly Janko Lucy Blasucci Jean A Jaglin 《Movement disorders》2003,18(10):1146-1149
Informed consent procedures in placebo-controlled trials are developed to ensure that subjects entering studies clearly understand the possibility of placebo assignment. The extent of patient understanding and the impact of learning that they were assigned placebo treatment have not been extensively studied. By using a standardized questionnaire, we interviewed 50 consecutive placebo-treated patients from 14 placebo-controlled clinical trials of Parkinson's disease (PD) after completion of their involvement. All patients interviewed understood that their study contained a placebo arm. All had hoped to receive the study drug rather than placebo, and more than half the subjects believed they had improved clinically during their placebo exposure. Positive impressions of enrollment in placebo-controlled trials were more frequent than negative, included helping to advance science (86%); liking the experience, education, and attention associated with the clinical trial (90%); and participating in research for the benefit of other patients as well as for themselves (80%). If another placebo-controlled trial was offered, 88% expressed that they would possibly, likely, or definitely be interested in enrollment. PD patients clearly understand the concept of placebo-controlled trials they complete them, but they are inaccurate in assessing whether they received placebo treatment. Although most wish they received the active compound being tested, the overall view of participation in placebo-controlled trials is viewed very positively by PD patients. 相似文献
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Disease Modification in Parkinson's Disease: Current Approaches,Challenges, and Future Considerations
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The greatest unmet therapeutic need in Parkinson's disease is the development of treatment that slows the relentless progression of the neurodegenerative process. The concept of “disease modification” encompasses intervention types ranging from those designed to slow the underlying degeneration to treatments directed at regenerating or replacing lost neurons. To date all attempts to develop effective disease‐modifying therapy have failed. Many reasons have been proposed for these failures including our rudimentary understanding of disease pathogenesis and the assumption that each targeted mechanisms of disease apply to most patients with the same clinical diagnosis. Here we review all aspects of this broad field including general concepts and past challenges followed by a discussion of treatment approaches under the following 4 categories: (1) α‐synuclein, (2) pathogenic mechanisms distinct from α‐synuclein (most also potentially triggered by α‐synuclein toxicity), (3) non‐SNCA genetic subtypes of “PD,” and (4) possible disease‐modifying interventions not directly influencing the underlying PD pathobiology. We emphasize treatments that are currently under active clinical development and highlight a wide range of important outstanding questions and concerns that will need to be considered to advance the field of disease modification in PD. Critically, it is unknown whether the dysfunctional molecular pathways/organelles amenable to modification occur in a sequential fashion across most clinically affected individuals or manifest differentially in independent molecular subtypes of PD. It is possible that there is no “order of disruption” applicable to most patients but, rather, “type of disruption” applicable to subtypes dependent on unknown factors, including genetic variability and other causes for heterogeneity in PD. Knowing when (early vs late), which (eg, synaptic transmission, endosomal sorting and maturation, lysosomal degradation, mitochondrial biogenesis), and in whom (PD subtype) specific disrupted cell pathways are truly pathogenic versus compensatory or even protective, will be important in considering the use of single or combined (“cocktails”) putative disease‐modifying therapies to selectively target these processes. Beyond the current phase 2 or 3 studies underway evaluating treatments directed at oxidative stress (inosine), cytosolic Ca2+ (isradipine), iron (deferiprone), and extracellular α‐synuclein (passive immunization), and upcoming trials of interventions affecting c‐Abl, glucagon‐like peptide‐1, and glucocerebrosidase, it might be argued that further trials in populations not enriched for the targeted pathogenic process are doomed to repeat the failures of the past. © 2018 International Parkinson and Movement Disorder Society 相似文献
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The placebo effect on bradykinesia in Parkinson's disease with and without prior drug conditioning
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Elisa Frisaldi PhD Elisa Carlino PhD Maurizio Zibetti MD PhD Diletta Barbiani MSc Francesca Dematteis MD Michele Lanotte MD Leonardo Lopiano MD PhD Fabrizio Benedetti MD 《Movement disorders》2017,32(10):1474-1478
Background : Placebo effects represent a major drawback in clinical trials, and their magnitude hampers the development of new treatments. Previous research showed that prior exposure to active treatments increases the placebo response for muscle rigidity in Parkinson's disease. Methods : We investigated the effects of prior exposure to apomorphine on the placebo response of another cardinal symptom of Parkinson's disease, bradykinesia, by a movement time analyzer. Results : We found no placebo response if the placebo was given for the first time, whereas the placebo response was substantial after prior pharmacological conditioning with apomorphine. Conclusions : These findings indicate that prior exposure to drugs is a critical factor in the occurrence and magnitude of placebo effects. These learning effects should be carefully assessed in clinical trials in which patients receive the active treatment first and then are randomized. Indeed, this sequence may generate high placebo responders. © 2017 International Parkinson and Movement Disorder Society 相似文献
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Christopher G. Goetz MD Joanne Wuu ScM Michael P. McDermott PhD Charles H. Adler MD PhD Stanley Fahn MD Curt R. Freed MD Robert A. Hauser MD Warren C. Olanow MD Ira Shoulson MD P.K. Tandon PhD Parkinson Study Group Sue Leurgans PhD 《Movement disorders》2008,23(5):690-699
Placebo‐associated improvements have been previously documented in small series of Parkinson's disease (PD) patients. Using a strict definition of placebo‐associated improvement, we examined rates and timing of placebo responses to identify patient‐ and study‐based characteristics, predicting positive placebo response in several PD clinical trials. We collected individual patient data from the placebo groups of 11 medical and surgical treatment trials involving PD patients with differing PD severities and placebo‐assignment likelihoods. We defined a positive placebo response as ≥50% improvement in total Unified Parkinson's Disease Rating Scale motor (UPDRSm) score or a decrease by ≥2 points on at least two UPDRSm items compared to baseline. We calculated positive placebo response rates at early (3–7 weeks), mid (8–18 weeks), and late (23–35 weeks) stages of follow‐up. Odds ratios for patient‐ and study‐based characteristics were obtained from a model fitted using generalized estimating equations. There were 858 patients on placebo who met inclusion criteria for analysis. Three studies involved patients without need of symptomatic treatment, two involved patients without motor fluctuations needing symptomatic treatment, and six (three medical and three surgical) involved patients with motor fluctuations. The overall placebo response rate was 16% (range: 0–55%). Patients with higher baseline UPDRSm scores and studies that focused on PD with motor fluctuations, surgical interventions, or those with a higher probability of placebo assignment showed increased odds of positive placebo response. Placebo responses were temporally distributed similarly during early, mid, and late phases of follow‐up. Placebo‐related improvements occur in most PD clinical trials and are similarly distributed across all 6 months of follow‐up. Recognition of factors that impact placebo response rates should be incorporated into individual study designs for PD clinical trials. © 2008 Movement Disorder Society 相似文献
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Parkinson Study Group 《Movement disorders》2013,28(13):1823-1831
Isradipine, a dihydropyridine calcium channel antagonist, has been shown to be neuroprotective in animal models of Parkinson's disease (PD). To establish a dosage of isradipine controlled‐release (CR) that is tolerable and demonstrates preliminary efficacy for use in a future pivotal efficacy trial a Phase 2, randomized, double‐blind, parallel group trial (Safety, Tolerability and Efficacy Assessment of Dynacirc CR in Parkinson Disease [STEADY‐PD]) was undertaken in subjects with early PD not requiring dopaminergic therapy (dopamine agonists or levodopa) randomized 1:1:1:1 to 5, 10, or 20 mg of isradipine CR or matching placebo daily. The primary outcome was tolerability defined as no more than a 30% difference in the proportion of patients completing the study on the originally assigned dosage between an active and placebo group. If more than one isradipine dosage was tolerable, then a 3‐point difference in total Unified Parkinson's Disease Rating Scale (UPDRS) change between baseline and week 52 (or time to sufficient disability to require dopaminergic therapy) was taken as a criterion for selection of the most desirable dosage for future study. STEADY‐PD enrolled 99 subjects. The tolerability of isradipine was dose dependent: placebo, 25 of 26 patients (96%); 5 mg, 19 of 23 patients (83%); 10 mg 19 of 26 patients (73%); and 20 mg 9 of 24 patients (37%). There was no difference in change in UPDRS among dosages. The most common adverse events were peripheral edema (30) and dizziness (24). Isradipine 10 mg daily was the maximal tolerable dosage in this study of early PD. A large placebo‐controlled trial will be necessary and is planned to assess efficacy of isradipine 10 mg daily to slow progression of PD disability. © 2013 International Parkinson and Movement Disorder Society. 相似文献
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To further characterize the short‐term levodopa response in early PD, we performed a retrospective analysis of the ELLDOPA study which randomized 361 early PD subjects to placebo, levodopa 150, 300, or 600 mg/day. We evaluated change in UPDRS motor scores (UPDRSm) from baseline to weeks 9 and 24, and identified changes in UPDRSm that best discriminated treatment with levodopa from placebo. Linear regressions were used to determine associations between baseline characteristics and changes in UPDRSm. Mean percent improvement in UPDRSm in levodopa‐treated subjects was greater than that for placebo‐treated subjects (27.4% vs. 5.8% at 9 weeks, P < 0.001 and 26.2% vs. 4.0% at 24 weeks, P < 0.001). UPDRSm change at 9 weeks ranged from –92.9% (improvement) to 85.7% (worsening) for levodopa and –86.7% to 160% for placebo, and at 24 weeks ranged from –100.0% to 242.9% for levodopa and –87.5% to 112.5% for placebo. UPDRSm improvements of 22.0% at 9 weeks and 23.8% at 24 weeks best discriminated treatment with levodopa 300 mg/day (a common initial maintenance dosage in clinical practice) from placebo. Significant associations were not observed between baseline subject characteristics and magnitude of response from baseline to week 24. We conclude that although levodopa treatment significantly improved PD signs when compared with placebo, there was a wide range and considerable overlap in clinical responses to levodopa and placebo. A substantial proportion of subjects with early PD did not experience a robust response to levodopa. An improvement in UPDRSm of ~22% best discriminated levodopa treatment from placebo. © 2009 Movement Disorder Society 相似文献
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Parkinson's disease (PD) is a neurodegenerative disorder characterized by loss of dopaminergic neurons in the substantia nigra and accumulation of iron and alpha-synuclein; it follows a characteristic pattern throughout the nervous system. Despite decades of successful preclinical neuroprotective studies, no drug has then shown efficacy in clinical trials. Considering this dilemma, we have reviewed and organized solutions of varying importance that can be exclusive or additive, and we outline approaches to help generate successful development of neuroprotective drugs for PD: (1) select patients in which the targeted mechanism is involved in the pathological process associated with the monitoring of target engagement, (2) combine treatments that target multiple pathways, (3) establish earliest interventions and develop better prodromal biomarkers, (4) adopt rigorous methodology and specific disease-relevant designs for disease-modifying clinical trials, (5) customize drug with better brain biodistribution, (6) prioritize repurposed drugs as a first line approach, and (7) adapt preclinical models to the targeted mechanisms with translational biomarkers to increase their predictive value. © 2020 International Parkinson and Movement Disorder Society 相似文献
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Christopher G. Goetz MD Eugene Laska PhD Christine Hicking Dipl Stat Philippe Damier MD PhD Thomas Müller MD John Nutt MD C. Warren Olanow MD Olivier Rascol MD PhD Hermann Russ MD PhD 《Movement disorders》2008,23(5):700-707
Clinical features that are prognostic indicators of placebo response among dyskinetic Parkinson's disease patients were determined. Placebo‐associated improvements occur in Parkinsonism, but responses in dyskinesia have not been studied. Placebo data from two multicenter studies with identical design comparing sarizotan to placebo for treating dyskinesia were accessed. Sarizotan (2 mg/day) failed to improve dyskinesia compared with placebo, but both treatments improved dyskinesia compared with baseline. Stepwise regression identified baseline characteristics that influenced dyskinesia response to placebo, and these factors were entered into a logistic regression model to quantify their influence on placebo‐related dyskinesia improvements and worsening. Because placebo‐associated improvements in Parkinsonism have been attributed to heightened dopaminergic activity, we also examined the association between changes in Parkinsonism and dyskinesia. Four hundred eighty‐four subjects received placebo treatment; 178 met criteria for placebo‐associated dyskinesia improvement and 37 for dyskinesia worsening. Older age, lower baseline Parkinsonism score, and lower total daily levodopa doses were associated with placebo‐associated improvement, whereas lower baseline dyskinesia score was associated with placebo‐associated worsening. Placebo‐associated dyskinesia changes were not correlated with Parkinsonism changes, and all effects in the sarizotan group were statistically explained by the placebo‐effect regression model. Dyskinesias are affected by placebo treatment. The absence of correlation between placebo‐induced changes in dyskinesia and Parkinsonism argues against a dopaminergic activation mechanism to explain placebo‐associated improvements in dyskinesia. The magnitude and variance of placebo‐related changes and the factors that influence them can be helpful in the design of future clinical trials of antidyskinetic agents. © 2007 Movement Disorder Society 相似文献
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Natalie Witek MD Glenn T. Stebbins PhD Christopher G. Goetz MD 《Movement disorders》2018,33(8):1204-1212
Placebo treatment is associated with clinical improvements in many medical conditions, but is particularly important in Parkinson's disease because improvements are common, marked, and associated with objective neurochemical and neurophysiologic changes. This review will focus on the effect of the placebo in patients with PD and will discuss the pathophysiology, observed characteristics of motor and nonmotor placebo responses, and the patient and study characteristics that modify the placebo response. Similar to the placebo response, nocebo and lessebo effects alter clinical trial outcomes and impact conclusions. Whereas placebo‐associated improvements are positively viewed by patients in clinical practice, they complicate clinical trials. The authors suggest strategies to reduce placebo effects during randomized placebo‐controlled trials evaluating new therapies. © 2018 International Parkinson and Movement Disorder Society 相似文献
12.
Dana Kim Young-Sam Kim Dong Wun Shin Chang-Shin Park Ju-Hee Kang 《JOURNAL OF CLINICAL NEUROLOGY》2016,12(4):381-392
No disease-modifying therapies (DMT) for neurodegenerative diseases (NDs) have been established, particularly for Alzheimer''s disease (AD) and Parkinson''s disease (PD). It is unclear why candidate drugs that successfully demonstrate therapeutic effects in animal models fail to show disease-modifying effects in clinical trials. To overcome this hurdle, patients with homogeneous pathologies should be detected as early as possible. The early detection of AD patients using sufficiently tested biomarkers could demonstrate the potential usefulness of combining biomarkers with clinical measures as a diagnostic tool. Cerebrospinal fluid (CSF) biomarkers for NDs are being incorporated in clinical trials designed with the aim of detecting patients earlier, evaluating target engagement, collecting homogeneous patients, facilitating prevention trials, and testing the potential of surrogate markers relative to clinical measures. In this review we summarize the latest information on CSF biomarkers in NDs, particularly AD and PD, and their use in clinical trials. The large number of issues related to CSF biomarker measurements and applications has resulted in relatively few clinical trials on CSF biomarkers being conducted. However, the available CSF biomarker data obtained in clinical trials support the advantages of incorporating CSF biomarkers in clinical trials, even though the data have mostly been obtained in AD trials. We describe the current issues with and ongoing efforts for the use of CSF biomarkers in clinical trials and the plans to harness CSF biomarkers for the development of DMT and clinical routines. This effort requires nationwide, global, and multidisciplinary efforts in academia, industry, and regulatory agencies to facilitate a new era. 相似文献
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Rodger J. Elble MD PhD Oksana Suchowersky MD Stephanie Shaftman MSc MS William J. Weiner MD Peng Huang PhD Barbara Tilley PhD On Behalf of the NINDS NET‐PD Investigators 《Movement disorders》2010,25(8):1082-1086
We explored the hypotheses that an investigator's belief in a putative neuroprotective agent might influence the timing of symptomatic intervention and the assessment of signs and symptoms of patients with Parkinson's disease with the Unified Parkinson's Disease Rating Scale (UPDRS). These hypotheses were tested with Cox and general linear modeling, using data from a previously published double‐blind placebo‐controlled futility trial of coenzyme Q10 and GPI‐1485. We found the investigators' level of confidence in these agents had no effect on the time to symptomatic therapy or on the change in UPDRS during 12 months of treatment. © 2010 Movement Disorder Society 相似文献
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Jean-Christophe Corvol MD Jean-Philippe Azulay MD Björn Bosse MSc Yves Dauvilliers MD Luc Defebvre MD Fabian Klostermann MD Norbert Kovacs MD David Maltête MD William G. Ondo MD Rajesh Pahwa MD Werner Rein MD Stéphane Thobois MD Martin Valis MD Aleksandar Videnovic MD Olivier Rascol MD for the THN- Study Investigators 《Movement disorders》2022,37(2):410-415
15.
Robert G. Hart MD Lesly A. Pearce MS Bernard M. Ravina MD Toby C. Yaltho MD John R. Marler MD 《Movement disorders》2009,24(5):647-654
Treatments to slow the progression are a major unmet need in Parkinson's disease. Detailed assessment of randomized trials testing putative neuroprotective drugs was undertaken to inform the design, reporting, and interpretation of future studies. This study is a systematic review of trials testing neuroprotective drugs. Data were extracted independently by two coauthors. Fifteen completed, published trials involving 4,087 participants tested 13 different drugs in 18 double‐blind comparisons with placebo. Seven comparisons involving 2,000 subjects assessed MAO‐B inhibitors. The primary outcome was change in the Unified Parkinson's Disease Rating Scale score in eight trials and time to need for dopaminergic therapy in seven. Mean participant age was 62 years, 35% were women, the interval from diagnosis to entry averaged 11 months, and the number of participants averaged 272 (largest = 806). Follow‐up averaged <16 months in all but two trials. Detailed randomization methods and success of double‐blinding were reported in 20% and 13%, respectively. Based on the investigators' conclusions, six trials were interpreted as consistent with a neuroprotective effect, three as negative, and five as either confounded or not meeting criteria for futility. Neuroprotection trials have involved relatively uniform groups of participants early in the clinical disease course, with outcomes weighted heavily toward motor deterioration. Future trials should include participants with wider ranges of disease stages and assess broader neurological outcomes. © 2008 Movement Disorder Society 相似文献
16.
Harnessing the power of placebos in movement disorders: Insights from Parkinson's disease in clinical research and practice
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Tiago A. Mestre MD MSc Michel Shamy MD FRCPC MSc Fabrizio Benedetti MD Anthony E. Lang MD FRCPC 《Movement disorders》2018,33(8):1195-1203
The placebo effect alongside the detrimental nocebo and lessebo effects associated with the use of placebos are well‐recognized phenomena. Research conducted in the last two decades has demonstrated that the placebo effect is a measurable health benefit with well‐known neurobiological correlates. In this review, we describe the current knowledge about how to best make use of the placebo effect to improve clinical research and optimize clinical care. We will cover four key topics: (1) setting the stage: historical perspectives on the use of placebos; (2) optimizing the use of placebos in clinical trials; (3) use of placebos in clinical practice; and (4) how can we minimize the ethical risks of using placebos? The adoption of the placebo‐controlled trial as a standard in the therapeutic development reduced the placebo effect to background noise in a therapeutic signal. Strategies to minimize the placebo effect in clinical trials have been used to obtain positive efficacy results. In more recent years, new study paradigms encouraged a change in the views on placebos and the placebo effect. Alternative study designs and the development of biomarkers for a placebo response permit a better understanding of the contribution of the placebo effect to the results of interventional studies, without minimizing it. In clinical practice, optimizing the placebo effect (and reducing nocebo effects) has the potential to improve care for our patients, but raises ethical challenges. An enhanced patient‐physician relationship would be central to any evidence‐based intervention used in clinical care to heighten the placebo effect. © 2018 International Parkinson and Movement Disorder Society 相似文献
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Anne Fink PhD Richard Dodel MD PhD Daniela Georges PhD Gabriele Doblhammer PhD 《Movement disorders》2023,38(11):2041-2052
Objective
The aim of our study is to analyze sex-specific patterns of Parkinson's disease dementia (PDD) incidence. We are investigating the extent to which sex differences in survival after initial Parkinson's disease (PD) diagnosis influence differences in PDD risk among PD patients.Methods
We used a random sample of German longitudinal health claims data of persons ages 50+ (2004–2019; n = 250,000) and identified new PD cases ages 65+ who were followed-up for a PDD diagnosis or death between 2006 and 2017. We performed Cox and competing-risk regression models, with death as competing event, to calculate PDD hazard ratios (HR) adjusted for age at PD onset, PD severity as measured by the modified Hoehn and Yahr (HY) scale, comorbidities, and medications.Results
Of 2195 new PD cases, 602 people died before PDD and 750 people developed PDD by the end of 2017. The adjusted risk of PDD differs by sex, with men having a higher PDD risk than women. When accounting for death, men and women do not differ in their PDD risk (HR = 1.02, P = 0.770). Sex-specific analyses showed significant age and severity effects in women (age: HR = 1.05, P < 0.001; HY 3–5 vs. 0–2.5: HR = 1.46, P = 0.011), but not in men.Conclusion
Older age at first PD diagnosis and higher disease severity increase PDD risk, but this association is attenuated for PD men when controlling for death. This implies that the most frail PD men die rapidly before receiving a dementia diagnosis, whereas women with PD survive at higher rates, regardless of their age at onset and disease severity. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. 相似文献20.
Francis P. Grenn BS Jonggeol J. Kim BA Mary B. Makarious BS Hirotaka Iwaki MD PhD Anastasia Illarionova Kajsa Brolin Jillian H. Kluss Artur F. Schumacher-Schuh MD PhD Hampton Leonard MSc Faraz Faghri PhD Kimberley Billingsley PhD Lynne Krohn MSc Ashley Hall MRes Monica Diez-Fairen Maria Teresa Periñán Jia Nee Foo PhD Cynthia Sandor PhD Caleb Webber PhD Brian K. Fiske PhD J. Raphael Gibbs PhD Mike A. Nalls PhD Andrew B. Singleton PhD Sara Bandres-Ciga PhD Xylena Reed PhD Cornelis Blauwendraat PhD the International Parkinson's Disease Genomics Consortium 《Movement disorders》2020,35(11):2056-2067