A "cure" for Parkinson's disease: can neuroprotection be proven with current trial designs?
Identifieur interne : 003476 ( PubMed/Corpus ); précédent : 003475; suivant : 003477A "cure" for Parkinson's disease: can neuroprotection be proven with current trial designs?
Auteurs : Carl E. ClarkeSource :
- Movement disorders : official journal of the Movement Disorder Society [ 0885-3185 ] ; 2004.
English descriptors
- KwdEn :
- Antiparkinson Agents (therapeutic use), Brain (blood supply), Brain (metabolism), Cost-Benefit Analysis, Dopamine Agonists (therapeutic use), Humans, Levodopa (therapeutic use), Neuroprotective Agents (therapeutic use), Parkinson Disease (diagnosis), Parkinson Disease (drug therapy), Parkinson Disease (economics), Quality of Life, Randomized Controlled Trials as Topic, Selegiline (therapeutic use), Tomography, Emission-Computed, Tomography, Emission-Computed, Single-Photon.
- MESH :
- chemical , therapeutic use : Antiparkinson Agents, Dopamine Agonists, Levodopa, Neuroprotective Agents, Selegiline.
- blood supply : Brain.
- diagnosis : Parkinson Disease.
- drug therapy : Parkinson Disease.
- economics : Parkinson Disease.
- metabolism : Brain.
- Cost-Benefit Analysis, Humans, Quality of Life, Randomized Controlled Trials as Topic, Tomography, Emission-Computed, Tomography, Emission-Computed, Single-Photon.
Abstract
Current medical and surgical therapies for Parkinson's disease provide symptomatic control of motor impairments rather than slowing or halting the progression of the disease. Previous clinical trials examining drugs such as dopamine agonists and selegiline for neuroprotective effects used "surrogate" outcomes, including clinical measures (rating scales, time to require levodopa), neuroimaging techniques (beta-CIT single photon emission computed tomography; fluorodopa positron emission tomography), and mortality tracking. These studies failed to provide conclusive results because of design faults such as failing to control for symptomatic effects, small sample size, and not accounting for the possible effects of drugs on radionuclide tracer handling. Lessons must be learned from these failed neuroprotection trials. This review summarises the problems with previous neuroprotection studies and makes recommendations for future trial design. It is concluded that the primary outcome of explanatory trials should continue to be clinical measures such as the Unified Parkinson's Disease Rating Scale (UPDRS). It should be assumed that all agents have a symptomatic effect, which necessitates evaluation after a prolonged drug washout period. To achieve the evaluation after a prolonged drug washout period more effectively, trials must be performed in early disease and over a short period (6-12 months) so that symptomatic therapy is not required. To achieve adequate statistical power, these trials will need to include thousands of patients. Radionuclide imaging can only be used in such trials after considerable methodological work has been performed to establish its validity and reliability. To be affordable, such large explanatory trials need more streamlined designs with fewer hospital visits, fewer outcome measures, and rationalised safety monitoring. The clinical effectiveness of promising compounds from explanatory trials will need to be established in large long-term pragmatic trials using outcome measures such as quality of life, cost-effectiveness, and mortality. Such pragmatic trials could be continuations of the explanatory trials: after the primary outcome of the explanatory study (e.g., UPDRS) has been reported in an interim analysis, the trial could be continued for a further 5 to 10 years to report on quality of life and health economics outcomes.
DOI: 10.1002/mds.20057
PubMed: 15133811
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pubmed:15133811Le document en format XML
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Clarke</name><affiliation><nlm:affiliation>Reader in Clinical Neurology, Division of Neuroscience, University of Birmingham and City Hospital, Birmingham, United Kingdom. c.e.clarke@bham.ac.uk</nlm:affiliation></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2004">2004</date><idno type="RBID">pubmed:15133811</idno><idno type="pmid">15133811</idno><idno type="doi">10.1002/mds.20057</idno><idno type="wicri:Area/PubMed/Corpus">003476</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">A "cure" for Parkinson's disease: can neuroprotection be proven with current trial designs?</title><author><name sortKey="Clarke, Carl E" sort="Clarke, Carl E" uniqKey="Clarke C" first="Carl E" last="Clarke">Carl E. 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Previous clinical trials examining drugs such as dopamine agonists and selegiline for neuroprotective effects used "surrogate" outcomes, including clinical measures (rating scales, time to require levodopa), neuroimaging techniques (beta-CIT single photon emission computed tomography; fluorodopa positron emission tomography), and mortality tracking. These studies failed to provide conclusive results because of design faults such as failing to control for symptomatic effects, small sample size, and not accounting for the possible effects of drugs on radionuclide tracer handling. Lessons must be learned from these failed neuroprotection trials. This review summarises the problems with previous neuroprotection studies and makes recommendations for future trial design. It is concluded that the primary outcome of explanatory trials should continue to be clinical measures such as the Unified Parkinson's Disease Rating Scale (UPDRS). It should be assumed that all agents have a symptomatic effect, which necessitates evaluation after a prolonged drug washout period. To achieve the evaluation after a prolonged drug washout period more effectively, trials must be performed in early disease and over a short period (6-12 months) so that symptomatic therapy is not required. To achieve adequate statistical power, these trials will need to include thousands of patients. Radionuclide imaging can only be used in such trials after considerable methodological work has been performed to establish its validity and reliability. To be affordable, such large explanatory trials need more streamlined designs with fewer hospital visits, fewer outcome measures, and rationalised safety monitoring. The clinical effectiveness of promising compounds from explanatory trials will need to be established in large long-term pragmatic trials using outcome measures such as quality of life, cost-effectiveness, and mortality. Such pragmatic trials could be continuations of the explanatory trials: after the primary outcome of the explanatory study (e.g., UPDRS) has been reported in an interim analysis, the trial could be continued for a further 5 to 10 years to report on quality of life and health economics outcomes.</div></front></TEI><pubmed><MedlineCitation Owner="NLM" Status="MEDLINE"><PMID Version="1">15133811</PMID><DateCreated><Year>2004</Year><Month>05</Month><Day>10</Day></DateCreated><DateCompleted><Year>2004</Year><Month>09</Month><Day>21</Day></DateCompleted><DateRevised><Year>2013</Year><Month>11</Month><Day>21</Day></DateRevised><Article PubModel="Print"><Journal><ISSN IssnType="Print">0885-3185</ISSN><JournalIssue CitedMedium="Print"><Volume>19</Volume><Issue>5</Issue><PubDate><Year>2004</Year><Month>May</Month></PubDate></JournalIssue><Title>Movement disorders : official journal of the Movement Disorder Society</Title><ISOAbbreviation>Mov. Disord.</ISOAbbreviation></Journal><ArticleTitle>A "cure" for Parkinson's disease: can neuroprotection be proven with current trial designs?</ArticleTitle><Pagination><MedlinePgn>491-8</MedlinePgn></Pagination><Abstract><AbstractText>Current medical and surgical therapies for Parkinson's disease provide symptomatic control of motor impairments rather than slowing or halting the progression of the disease. Previous clinical trials examining drugs such as dopamine agonists and selegiline for neuroprotective effects used "surrogate" outcomes, including clinical measures (rating scales, time to require levodopa), neuroimaging techniques (beta-CIT single photon emission computed tomography; fluorodopa positron emission tomography), and mortality tracking. These studies failed to provide conclusive results because of design faults such as failing to control for symptomatic effects, small sample size, and not accounting for the possible effects of drugs on radionuclide tracer handling. Lessons must be learned from these failed neuroprotection trials. This review summarises the problems with previous neuroprotection studies and makes recommendations for future trial design. It is concluded that the primary outcome of explanatory trials should continue to be clinical measures such as the Unified Parkinson's Disease Rating Scale (UPDRS). It should be assumed that all agents have a symptomatic effect, which necessitates evaluation after a prolonged drug washout period. To achieve the evaluation after a prolonged drug washout period more effectively, trials must be performed in early disease and over a short period (6-12 months) so that symptomatic therapy is not required. To achieve adequate statistical power, these trials will need to include thousands of patients. Radionuclide imaging can only be used in such trials after considerable methodological work has been performed to establish its validity and reliability. To be affordable, such large explanatory trials need more streamlined designs with fewer hospital visits, fewer outcome measures, and rationalised safety monitoring. The clinical effectiveness of promising compounds from explanatory trials will need to be established in large long-term pragmatic trials using outcome measures such as quality of life, cost-effectiveness, and mortality. Such pragmatic trials could be continuations of the explanatory trials: after the primary outcome of the explanatory study (e.g., UPDRS) has been reported in an interim analysis, the trial could be continued for a further 5 to 10 years to report on quality of life and health economics outcomes.</AbstractText><CopyrightInformation>Copyright 2004 Movement Disorder Society</CopyrightInformation></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Clarke</LastName><ForeName>Carl E</ForeName><Initials>CE</Initials><AffiliationInfo><Affiliation>Reader in Clinical Neurology, Division of Neuroscience, University of Birmingham and City Hospital, Birmingham, United Kingdom. c.e.clarke@bham.ac.uk</Affiliation></AffiliationInfo></Author></AuthorList><Language>eng</Language><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType><PublicationType UI="D013485">Research Support, Non-U.S. Gov't</PublicationType><PublicationType UI="D016454">Review</PublicationType></PublicationTypeList></Article><MedlineJournalInfo><Country>United States</Country><MedlineTA>Mov Disord</MedlineTA><NlmUniqueID>8610688</NlmUniqueID><ISSNLinking>0885-3185</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D000978">Antiparkinson Agents</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D018491">Dopamine Agonists</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D018696">Neuroprotective Agents</NameOfSubstance></Chemical><Chemical><RegistryNumber>14611-51-9</RegistryNumber><NameOfSubstance UI="D012642">Selegiline</NameOfSubstance></Chemical><Chemical><RegistryNumber>46627O600J</RegistryNumber><NameOfSubstance UI="D007980">Levodopa</NameOfSubstance></Chemical></ChemicalList><CitationSubset>IM</CitationSubset><MeshHeadingList><MeshHeading><DescriptorName MajorTopicYN="N" UI="D000978">Antiparkinson Agents</DescriptorName><QualifierName MajorTopicYN="Y" UI="Q000627">therapeutic use</QualifierName></MeshHeading><MeshHeading><DescriptorName MajorTopicYN="N" UI="D001921">Brain</DescriptorName><QualifierName MajorTopicYN="N" UI="Q000098">blood supply</QualifierName><QualifierName MajorTopicYN="N" UI="Q000378">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName MajorTopicYN="N" UI="D003362">Cost-Benefit Analysis</DescriptorName></MeshHeading><MeshHeading><DescriptorName MajorTopicYN="N" UI="D018491">Dopamine Agonists</DescriptorName><QualifierName MajorTopicYN="Y" UI="Q000627">therapeutic use</QualifierName></MeshHeading><MeshHeading><DescriptorName MajorTopicYN="N" UI="D006801">Humans</DescriptorName></MeshHeading><MeshHeading><DescriptorName MajorTopicYN="N" UI="D007980">Levodopa</DescriptorName><QualifierName MajorTopicYN="Y" UI="Q000627">therapeutic use</QualifierName></MeshHeading><MeshHeading><DescriptorName MajorTopicYN="N" UI="D018696">Neuroprotective Agents</DescriptorName><QualifierName MajorTopicYN="Y" UI="Q000627">therapeutic use</QualifierName></MeshHeading><MeshHeading><DescriptorName MajorTopicYN="N" UI="D010300">Parkinson Disease</DescriptorName><QualifierName MajorTopicYN="N" UI="Q000175">diagnosis</QualifierName><QualifierName MajorTopicYN="Y" UI="Q000188">drug therapy</QualifierName><QualifierName MajorTopicYN="N" UI="Q000191">economics</QualifierName></MeshHeading><MeshHeading><DescriptorName MajorTopicYN="N" UI="D011788">Quality of Life</DescriptorName></MeshHeading><MeshHeading><DescriptorName MajorTopicYN="N" UI="D016032">Randomized Controlled Trials as Topic</DescriptorName></MeshHeading><MeshHeading><DescriptorName MajorTopicYN="N" UI="D012642">Selegiline</DescriptorName><QualifierName MajorTopicYN="Y" UI="Q000627">therapeutic use</QualifierName></MeshHeading><MeshHeading><DescriptorName MajorTopicYN="N" UI="D014055">Tomography, Emission-Computed</DescriptorName></MeshHeading><MeshHeading><DescriptorName MajorTopicYN="N" UI="D015899">Tomography, Emission-Computed, Single-Photon</DescriptorName></MeshHeading></MeshHeadingList><NumberOfReferences>27</NumberOfReferences></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="pubmed"><Year>2004</Year><Month>5</Month><Day>11</Day><Hour>5</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2004</Year><Month>9</Month><Day>24</Day><Hour>5</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2004</Year><Month>5</Month><Day>11</Day><Hour>5</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>ppublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">15133811</ArticleId><ArticleId IdType="doi">10.1002/mds.20057</ArticleId></ArticleIdList></PubmedData></pubmed></record>Pour manipuler ce document sous Unix (Dilib)
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