Are delayed-start design trials to show neuroprotection in Parkinson's disease fundamentally flawed?
Identifieur interne : 002353 ( PubMed/Corpus ); précédent : 002352; suivant : 002354Are delayed-start design trials to show neuroprotection in Parkinson's disease fundamentally flawed?
Auteurs : Carl E. ClarkeSource :
- Movement disorders : official journal of the Movement Disorder Society [ 1531-8257 ] ; 2008.
English descriptors
- KwdEn :
- MESH :
- chemical , physiology : Dopamine.
- drug therapy : Parkinson Disease.
- physiology : Neurons.
- physiopathology : Parkinson Disease.
- standards : Research Design.
- chemical , therapeutic use : Neuroprotective Agents.
- Clinical Trials as Topic, Disease Progression, Humans, Models, Biological.
Abstract
Considerable effort has gone into preclinical neuroprotection research in Parkinson's disease (PD) and several large clinical trials have been mounted, but no agent has been conclusively shown to be protective. The latest innovation in PD neuroprotection trial design is the delayed-start design trial. If patients with early PD do better after 12 to 18 months of immediate drug therapy compared to those in whom it is delayed for 6 to 9 months, this is attributed to a neuroprotective effect. However, delayed-start design trials may be fundamentally flawed. It has been suggested that physiological mechanisms compensating for the loss of dopaminergic neurones in early PD may be deleterious and that immediate treatment may prevent such mechanisms and thereby be neuroprotective. If this hypothesis is correct, any drug with a symptomatic effect will be neuroprotective in early PD and delayed-start design trials will show this generic effect, not a neuroprotective effect specific to the drug. Delayed-start design trials require patients to potentially stay untreated for 6 to 9 months. This may lead to the selection of slowly progressive types of PD, such as that in younger patients and those with tremor-dominant disease, so the results may not be generalizable to the majority of patients. Delayed-start design trials are powered to find small differences in total UPDRS score which may not be clinically significant; larger and longer placebo-controlled trials are required to confirm the clinical significance of their findings. These arguments add to the growing tide of opinion for a fundamental rethink of our policy toward neuroprotection research in PD.
DOI: 10.1002/mds.21918
PubMed: 18175348
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Clarke</name><affiliation><nlm:affiliation>Department of Neurology, City Hospital, Sandwell and West Birmingham Hospitals NHS Trust, Birmingham, United Kingdom. c.e.clarke@bham.ac.uk</nlm:affiliation></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2008">2008</date><idno type="doi">10.1002/mds.21918</idno><idno type="RBID">pubmed:18175348</idno><idno type="pmid">18175348</idno><idno type="wicri:Area/PubMed/Corpus">002353</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">Are delayed-start design trials to show neuroprotection in Parkinson's disease fundamentally flawed?</title><author><name sortKey="Clarke, Carl E" sort="Clarke, Carl E" uniqKey="Clarke C" first="Carl E" last="Clarke">Carl E. Clarke</name><affiliation><nlm:affiliation>Department of Neurology, City Hospital, Sandwell and West Birmingham Hospitals NHS Trust, Birmingham, United Kingdom. c.e.clarke@bham.ac.uk</nlm:affiliation></affiliation></author></analytic><series><title level="j">Movement disorders : official journal of the Movement Disorder Society</title><idno type="eISSN">1531-8257</idno><imprint><date when="2008" type="published">2008</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Clinical Trials as Topic</term><term>Disease Progression</term><term>Dopamine (physiology)</term><term>Humans</term><term>Models, Biological</term><term>Neurons (physiology)</term><term>Neuroprotective Agents (therapeutic use)</term><term>Parkinson Disease (drug therapy)</term><term>Parkinson Disease (physiopathology)</term><term>Research Design (standards)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="physiology" xml:lang="en"><term>Dopamine</term></keywords><keywords scheme="MESH" qualifier="drug therapy" xml:lang="en"><term>Parkinson Disease</term></keywords><keywords scheme="MESH" qualifier="physiology" xml:lang="en"><term>Neurons</term></keywords><keywords scheme="MESH" qualifier="physiopathology" xml:lang="en"><term>Parkinson Disease</term></keywords><keywords scheme="MESH" qualifier="standards" xml:lang="en"><term>Research Design</term></keywords><keywords scheme="MESH" type="chemical" qualifier="therapeutic use" xml:lang="en"><term>Neuroprotective Agents</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Clinical Trials as Topic</term><term>Disease Progression</term><term>Humans</term><term>Models, Biological</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Considerable effort has gone into preclinical neuroprotection research in Parkinson's disease (PD) and several large clinical trials have been mounted, but no agent has been conclusively shown to be protective. The latest innovation in PD neuroprotection trial design is the delayed-start design trial. If patients with early PD do better after 12 to 18 months of immediate drug therapy compared to those in whom it is delayed for 6 to 9 months, this is attributed to a neuroprotective effect. However, delayed-start design trials may be fundamentally flawed. It has been suggested that physiological mechanisms compensating for the loss of dopaminergic neurones in early PD may be deleterious and that immediate treatment may prevent such mechanisms and thereby be neuroprotective. If this hypothesis is correct, any drug with a symptomatic effect will be neuroprotective in early PD and delayed-start design trials will show this generic effect, not a neuroprotective effect specific to the drug. Delayed-start design trials require patients to potentially stay untreated for 6 to 9 months. This may lead to the selection of slowly progressive types of PD, such as that in younger patients and those with tremor-dominant disease, so the results may not be generalizable to the majority of patients. Delayed-start design trials are powered to find small differences in total UPDRS score which may not be clinically significant; larger and longer placebo-controlled trials are required to confirm the clinical significance of their findings. These arguments add to the growing tide of opinion for a fundamental rethink of our policy toward neuroprotection research in PD.</div></front></TEI><pubmed><MedlineCitation Owner="NLM" Status="MEDLINE"><PMID Version="1">18175348</PMID><DateCreated><Year>2008</Year><Month>05</Month><Day>01</Day></DateCreated><DateCompleted><Year>2008</Year><Month>08</Month><Day>06</Day></DateCompleted><DateRevised><Year>2013</Year><Month>11</Month><Day>21</Day></DateRevised><Article PubModel="Print"><Journal><ISSN IssnType="Electronic">1531-8257</ISSN><JournalIssue CitedMedium="Internet"><Volume>23</Volume><Issue>6</Issue><PubDate><Year>2008</Year><Month>Apr</Month><Day>30</Day></PubDate></JournalIssue><Title>Movement disorders : official journal of the Movement Disorder Society</Title><ISOAbbreviation>Mov. Disord.</ISOAbbreviation></Journal><ArticleTitle>Are delayed-start design trials to show neuroprotection in Parkinson's disease fundamentally flawed?</ArticleTitle><Pagination><MedlinePgn>784-9</MedlinePgn></Pagination><ELocationID EIdType="doi" ValidYN="Y">10.1002/mds.21918</ELocationID><Abstract><AbstractText>Considerable effort has gone into preclinical neuroprotection research in Parkinson's disease (PD) and several large clinical trials have been mounted, but no agent has been conclusively shown to be protective. The latest innovation in PD neuroprotection trial design is the delayed-start design trial. If patients with early PD do better after 12 to 18 months of immediate drug therapy compared to those in whom it is delayed for 6 to 9 months, this is attributed to a neuroprotective effect. However, delayed-start design trials may be fundamentally flawed. It has been suggested that physiological mechanisms compensating for the loss of dopaminergic neurones in early PD may be deleterious and that immediate treatment may prevent such mechanisms and thereby be neuroprotective. If this hypothesis is correct, any drug with a symptomatic effect will be neuroprotective in early PD and delayed-start design trials will show this generic effect, not a neuroprotective effect specific to the drug. Delayed-start design trials require patients to potentially stay untreated for 6 to 9 months. This may lead to the selection of slowly progressive types of PD, such as that in younger patients and those with tremor-dominant disease, so the results may not be generalizable to the majority of patients. Delayed-start design trials are powered to find small differences in total UPDRS score which may not be clinically significant; larger and longer placebo-controlled trials are required to confirm the clinical significance of their findings. These arguments add to the growing tide of opinion for a fundamental rethink of our policy toward neuroprotection research in PD.</AbstractText><CopyrightInformation>(c) 2008 Movement Disorder Society.</CopyrightInformation></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Clarke</LastName><ForeName>Carl E</ForeName><Initials>CE</Initials><AffiliationInfo><Affiliation>Department of Neurology, City Hospital, Sandwell and West Birmingham Hospitals NHS Trust, Birmingham, United Kingdom. c.e.clarke@bham.ac.uk</Affiliation></AffiliationInfo></Author></AuthorList><Language>eng</Language><PublicationTypeList><PublicationType UI="D016428">Journal Article</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="D018696">Neuroprotective Agents</NameOfSubstance></Chemical><Chemical><RegistryNumber>VTD58H1Z2X</RegistryNumber><NameOfSubstance UI="D004298">Dopamine</NameOfSubstance></Chemical></ChemicalList><CitationSubset>IM</CitationSubset><CommentsCorrectionsList><CommentsCorrections RefType="CommentIn"><RefSource>Mov Disord. 2009 Jan 15;24(1):153-4</RefSource><PMID Version="1">18649387</PMID></CommentsCorrections></CommentsCorrectionsList><MeshHeadingList><MeshHeading><DescriptorName MajorTopicYN="Y" UI="D002986">Clinical Trials as Topic</DescriptorName></MeshHeading><MeshHeading><DescriptorName MajorTopicYN="N" UI="D018450">Disease Progression</DescriptorName></MeshHeading><MeshHeading><DescriptorName MajorTopicYN="N" UI="D004298">Dopamine</DescriptorName><QualifierName MajorTopicYN="N" UI="Q000502">physiology</QualifierName></MeshHeading><MeshHeading><DescriptorName MajorTopicYN="N" UI="D006801">Humans</DescriptorName></MeshHeading><MeshHeading><DescriptorName MajorTopicYN="N" UI="D008954">Models, Biological</DescriptorName></MeshHeading><MeshHeading><DescriptorName MajorTopicYN="N" UI="D009474">Neurons</DescriptorName><QualifierName MajorTopicYN="N" UI="Q000502">physiology</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="Y" UI="Q000188">drug therapy</QualifierName><QualifierName MajorTopicYN="Y" UI="Q000503">physiopathology</QualifierName></MeshHeading><MeshHeading><DescriptorName MajorTopicYN="N" UI="D012107">Research Design</DescriptorName><QualifierName MajorTopicYN="Y" UI="Q000592">standards</QualifierName></MeshHeading></MeshHeadingList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="pubmed"><Year>2008</Year><Month>1</Month><Day>5</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2008</Year><Month>8</Month><Day>7</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2008</Year><Month>1</Month><Day>5</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>ppublish</PublicationStatus><ArticleIdList><ArticleId IdType="doi">10.1002/mds.21918</ArticleId><ArticleId IdType="pubmed">18175348</ArticleId></ArticleIdList></PubmedData></pubmed></record>Pour manipuler ce document sous Unix (Dilib)
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