Safety and efficacy of perampanel in advanced Parkinson's disease: A randomized, placebo‐controlled study
Identifieur interne : 000052 ( Istex/Corpus ); précédent : 000051; suivant : 000053Safety and efficacy of perampanel in advanced Parkinson's disease: A randomized, placebo‐controlled study
Auteurs : Karla Eggert ; David Squillacote ; Paolo Barone ; Richard Dodel ; Regina Katzenschlager ; Murat Emre ; Andrew J. Lees ; Olivier Rascol ; Werner Poewe ; Eduardo Tolosa ; Claudia Trenkwalder ; Marco Onofrj ; Fabrizio Stocchi ; Giuseppe Nappi ; Vladimir Kostic ; Jagoda Potic ; Evzen Ruzicka ; Wolfgang OertelSource :
- Movement Disorders [ 0885-3185 ] ; 2010-05-15.
English descriptors
Abstract
Perampanel, a novel, noncompetitive, selective AMPA‐receptor antagonist demonstrated evidence of efficacy in reducing motor symptoms in animal models of Parkinson's disease (PD). We assessed the safety and efficacy of perampanel for treatment of “wearing off” motor fluctuations in patients with PD. Patients (N = 263) were randomly assigned to once‐daily add‐on 0.5, 1, or 2 mg of perampanel or placebo. The primary objective was to determine whether there was a dose‐response relationship for efficacy among the 3 perampanel doses and placebo. The primary efficacy endpoint for each treatment was measured as the least‐squares (LS) mean change from baseline to week 12 in percent “off” time reduction during the waking day, as recorded by patient diaries. The primary efficacy analysis was a 1‐sided Williams test for dose‐response trend at the 0.025 level of significance. At week 12, dose‐response trends, as determined by the Williams test, were not statistically significant for LS mean reduction in percent “off” time during the waking day (P = 0.061, with significance defined as P ≤ 0.025). The 2 higher perampanel doses (ITT population; n = 258) produced nonsignificant reductions from baseline to week 12 in percent “off” time during the waking day versus placebo (7.59%, P= 0.421 [1 mg], 8.60%, P = 0.257 [2 mg] versus 5.05% [placebo]; significance for pairwise comparisons defined as P ≤ 0.05). There were no significant changes in dyskinesia or cognitive function in any perampanel group versus placebo. Adverse events were similar across treatment groups. Perampanel treatment was well tolerated and safe, but failed to achieve statistical significance in primary and secondary endpoints. © 2010 Movement Disorder Society
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DOI: 10.1002/mds.22974
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<record><TEI wicri:istexFullTextTei="biblStruct"><teiHeader><fileDesc><titleStmt><title xml:lang="en">Safety and efficacy of perampanel in advanced Parkinson's disease: A randomized, placebo‐controlled study</title><author><name sortKey="Eggert, Karla" sort="Eggert, Karla" uniqKey="Eggert K" first="Karla" last="Eggert">Karla Eggert</name><affiliation><mods:affiliation>German Competence Network on Parkinson's Disease, Department of Neurology, Philipps‐University Marburg, Marburg, Germany</mods:affiliation></affiliation></author><author><name sortKey="Squillacote, David" sort="Squillacote, David" uniqKey="Squillacote D" first="David" last="Squillacote">David Squillacote</name><affiliation><mods:affiliation>Eisai Global Clinical Development, Eisai Medical Research Inc., Woodcliff Lake, New Jersey, USA</mods:affiliation></affiliation></author><author><name sortKey="Barone, Paolo" sort="Barone, Paolo" uniqKey="Barone P" first="Paolo" last="Barone">Paolo Barone</name><affiliation><mods:affiliation>Department of Neurological Sciences, University of Naples Federico II‐IDC Hermitage‐Capodimonte, Naples, Italy</mods:affiliation></affiliation></author><author><name sortKey="Dodel, Richard" sort="Dodel, Richard" uniqKey="Dodel R" first="Richard" last="Dodel">Richard Dodel</name><affiliation><mods:affiliation>Department of Neurology, Rheinische Friedrich‐Wilhelms‐University, Bonn, Germany</mods:affiliation></affiliation></author><author><name sortKey="Katzenschlager, Regina" sort="Katzenschlager, Regina" uniqKey="Katzenschlager R" first="Regina" last="Katzenschlager">Regina Katzenschlager</name><affiliation><mods:affiliation>Department of Neurology, Donauspital, Vienna, Austria</mods:affiliation></affiliation></author><author><name sortKey="Emre, Murat" sort="Emre, Murat" uniqKey="Emre M" first="Murat" last="Emre">Murat Emre</name><affiliation><mods:affiliation>Department of Neurology, Istanbul Medical School, Istanbul, Turkey</mods:affiliation></affiliation></author><author><name sortKey="Lees, Andrew J" sort="Lees, Andrew J" uniqKey="Lees A" first="Andrew J." last="Lees">Andrew J. 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Mondino Institute of Neurology” Foundation, Pavia, Italy</mods:affiliation></affiliation></author><author><name sortKey="Kostic, Vladimir" sort="Kostic, Vladimir" uniqKey="Kostic V" first="Vladimir" last="Kostic">Vladimir Kostic</name><affiliation><mods:affiliation>Institute of Neurology, Clinical Centre of Serbia, Belgrade, Serbia</mods:affiliation></affiliation></author><author><name sortKey="Potic, Jagoda" sort="Potic, Jagoda" uniqKey="Potic J" first="Jagoda" last="Potic">Jagoda Potic</name><affiliation><mods:affiliation>Clinic for Neurology and Psychiatry, Clinical Hospital Centre “Zvezdara,” Belgrade, Serbia</mods:affiliation></affiliation></author><author><name sortKey="Ruzicka, Evzen" sort="Ruzicka, Evzen" uniqKey="Ruzicka E" first="Evzen" last="Ruzicka">Evzen Ruzicka</name><affiliation><mods:affiliation>Department of Neurology, Charles University in Prague, 1st Faculty of Medicine and General Teaching Hospital, Prague, Czech Republic</mods:affiliation></affiliation></author><author><name sortKey="Oertel, Wolfgang" sort="Oertel, Wolfgang" uniqKey="Oertel W" first="Wolfgang" last="Oertel">Wolfgang Oertel</name><affiliation><mods:affiliation>German Competence Network on Parkinson's Disease, Department of Neurology, Philipps‐University Marburg, Marburg, Germany</mods:affiliation></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">ISTEX</idno><idno type="RBID">ISTEX:F3991B9F741986E5D89C72FDB4FA8C332024F02F</idno><date when="2010" year="2010">2010</date><idno type="doi">10.1002/mds.22974</idno><idno type="url">https://api.istex.fr/document/F3991B9F741986E5D89C72FDB4FA8C332024F02F/fulltext/pdf</idno><idno type="wicri:Area/Istex/Corpus">000052</idno></publicationStmt><sourceDesc><biblStruct><analytic><title level="a" type="main" xml:lang="en">Safety and efficacy of perampanel in advanced Parkinson's disease: A randomized, placebo‐controlled study</title><author><name sortKey="Eggert, Karla" sort="Eggert, Karla" uniqKey="Eggert K" first="Karla" last="Eggert">Karla Eggert</name><affiliation><mods:affiliation>German Competence Network on Parkinson's Disease, Department of Neurology, Philipps‐University Marburg, Marburg, Germany</mods:affiliation></affiliation></author><author><name sortKey="Squillacote, David" sort="Squillacote, David" uniqKey="Squillacote D" first="David" last="Squillacote">David Squillacote</name><affiliation><mods:affiliation>Eisai Global Clinical Development, Eisai Medical Research Inc., Woodcliff Lake, New Jersey, USA</mods:affiliation></affiliation></author><author><name sortKey="Barone, Paolo" sort="Barone, Paolo" uniqKey="Barone P" first="Paolo" last="Barone">Paolo Barone</name><affiliation><mods:affiliation>Department of Neurological Sciences, University of Naples Federico II‐IDC Hermitage‐Capodimonte, Naples, Italy</mods:affiliation></affiliation></author><author><name sortKey="Dodel, Richard" sort="Dodel, Richard" uniqKey="Dodel R" first="Richard" last="Dodel">Richard Dodel</name><affiliation><mods:affiliation>Department of Neurology, Rheinische Friedrich‐Wilhelms‐University, Bonn, Germany</mods:affiliation></affiliation></author><author><name sortKey="Katzenschlager, Regina" sort="Katzenschlager, Regina" uniqKey="Katzenschlager R" first="Regina" last="Katzenschlager">Regina Katzenschlager</name><affiliation><mods:affiliation>Department of Neurology, Donauspital, Vienna, Austria</mods:affiliation></affiliation></author><author><name sortKey="Emre, Murat" sort="Emre, Murat" uniqKey="Emre M" first="Murat" last="Emre">Murat Emre</name><affiliation><mods:affiliation>Department of Neurology, Istanbul Medical School, Istanbul, Turkey</mods:affiliation></affiliation></author><author><name sortKey="Lees, Andrew J" sort="Lees, Andrew J" uniqKey="Lees A" first="Andrew J." last="Lees">Andrew J. Lees</name><affiliation><mods:affiliation>Reta Lila Weston Institute of Neurological Studies, University College London, London, United Kingdom</mods:affiliation></affiliation></author><author><name sortKey="Rascol, Olivier" sort="Rascol, Olivier" uniqKey="Rascol O" first="Olivier" last="Rascol">Olivier Rascol</name><affiliation><mods:affiliation>Clinical Investigation Center, INSERM CIC9302, University Hospital Toulouse, Toulouse, France</mods:affiliation></affiliation><affiliation><mods:affiliation>Departments of Clinical Pharmacology and Neurosciences, INSERM UMR825, University Hospital Toulouse, Toulouse, France</mods:affiliation></affiliation></author><author><name sortKey="Poewe, Werner" sort="Poewe, Werner" uniqKey="Poewe W" first="Werner" last="Poewe">Werner Poewe</name><affiliation><mods:affiliation>Department of Neurology, Medical University Innsbruck, Innsbruck, Austria</mods:affiliation></affiliation></author><author><name sortKey="Tolosa, Eduardo" sort="Tolosa, Eduardo" uniqKey="Tolosa E" first="Eduardo" last="Tolosa">Eduardo Tolosa</name><affiliation><mods:affiliation>Neurology Service, Hospital Clinic, Universitat de Barcelona, CIBERNED, Barcelona, Spain</mods:affiliation></affiliation></author><author><name sortKey="Trenkwalder, Claudia" sort="Trenkwalder, Claudia" uniqKey="Trenkwalder C" first="Claudia" last="Trenkwalder">Claudia Trenkwalder</name><affiliation><mods:affiliation>Paracelsus‐Elena Klinik, Kassel, Germany</mods:affiliation></affiliation></author><author><name sortKey="Onofrj, Marco" sort="Onofrj, Marco" uniqKey="Onofrj M" first="Marco" last="Onofrj">Marco Onofrj</name><affiliation><mods:affiliation>Clinica Neurologica, Università Chieti‐Pescara, Italy</mods:affiliation></affiliation></author><author><name sortKey="Stocchi, Fabrizio" sort="Stocchi, Fabrizio" uniqKey="Stocchi F" first="Fabrizio" last="Stocchi">Fabrizio Stocchi</name><affiliation><mods:affiliation>Department of Neurology, IRCCS San Raffaele, Rome, Italy</mods:affiliation></affiliation></author><author><name sortKey="Nappi, Giuseppe" sort="Nappi, Giuseppe" uniqKey="Nappi G" first="Giuseppe" last="Nappi">Giuseppe Nappi</name><affiliation><mods:affiliation>Chair of Neurology, University “La Sapienza,” Rome, Italy</mods:affiliation></affiliation><affiliation><mods:affiliation>IRCCS “C. Mondino Institute of Neurology” Foundation, Pavia, Italy</mods:affiliation></affiliation></author><author><name sortKey="Kostic, Vladimir" sort="Kostic, Vladimir" uniqKey="Kostic V" first="Vladimir" last="Kostic">Vladimir Kostic</name><affiliation><mods:affiliation>Institute of Neurology, Clinical Centre of Serbia, Belgrade, Serbia</mods:affiliation></affiliation></author><author><name sortKey="Potic, Jagoda" sort="Potic, Jagoda" uniqKey="Potic J" first="Jagoda" last="Potic">Jagoda Potic</name><affiliation><mods:affiliation>Clinic for Neurology and Psychiatry, Clinical Hospital Centre “Zvezdara,” Belgrade, Serbia</mods:affiliation></affiliation></author><author><name sortKey="Ruzicka, Evzen" sort="Ruzicka, Evzen" uniqKey="Ruzicka E" first="Evzen" last="Ruzicka">Evzen Ruzicka</name><affiliation><mods:affiliation>Department of Neurology, Charles University in Prague, 1st Faculty of Medicine and General Teaching Hospital, Prague, Czech Republic</mods:affiliation></affiliation></author><author><name sortKey="Oertel, Wolfgang" sort="Oertel, Wolfgang" uniqKey="Oertel W" first="Wolfgang" last="Oertel">Wolfgang Oertel</name><affiliation><mods:affiliation>German Competence Network on Parkinson's Disease, Department of Neurology, Philipps‐University Marburg, Marburg, Germany</mods:affiliation></affiliation></author></analytic><monogr></monogr><series><title level="j">Movement Disorders</title><title level="j" type="abbrev">Mov. Disord.</title><idno type="ISSN">0885-3185</idno><idno type="eISSN">1531-8257</idno><imprint><publisher>Wiley Subscription Services, Inc., A Wiley Company</publisher><pubPlace>Hoboken</pubPlace><date type="published" when="2010-05-15">2010-05-15</date><biblScope unit="vol">25</biblScope><biblScope unit="issue">7</biblScope><biblScope unit="page" from="896">896</biblScope><biblScope unit="page" to="905">905</biblScope></imprint><idno type="ISSN">0885-3185</idno></series><idno type="istex">F3991B9F741986E5D89C72FDB4FA8C332024F02F</idno><idno type="DOI">10.1002/mds.22974</idno><idno type="ArticleID">MDS22974</idno></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0885-3185</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>AMPA receptor antagonist</term><term>Parkinson's disease</term><term>dyskinesia</term><term>motor fluctuations</term><term>perampanel</term></keywords></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Perampanel, a novel, noncompetitive, selective AMPA‐receptor antagonist demonstrated evidence of efficacy in reducing motor symptoms in animal models of Parkinson's disease (PD). We assessed the safety and efficacy of perampanel for treatment of “wearing off” motor fluctuations in patients with PD. Patients (N = 263) were randomly assigned to once‐daily add‐on 0.5, 1, or 2 mg of perampanel or placebo. The primary objective was to determine whether there was a dose‐response relationship for efficacy among the 3 perampanel doses and placebo. The primary efficacy endpoint for each treatment was measured as the least‐squares (LS) mean change from baseline to week 12 in percent “off” time reduction during the waking day, as recorded by patient diaries. The primary efficacy analysis was a 1‐sided Williams test for dose‐response trend at the 0.025 level of significance. At week 12, dose‐response trends, as determined by the Williams test, were not statistically significant for LS mean reduction in percent “off” time during the waking day (P = 0.061, with significance defined as P ≤ 0.025). The 2 higher perampanel doses (ITT population; n = 258) produced nonsignificant reductions from baseline to week 12 in percent “off” time during the waking day versus placebo (7.59%, P= 0.421 [1 mg], 8.60%, P = 0.257 [2 mg] versus 5.05% [placebo]; significance for pairwise comparisons defined as P ≤ 0.05). There were no significant changes in dyskinesia or cognitive function in any perampanel group versus placebo. Adverse events were similar across treatment groups. Perampanel treatment was well tolerated and safe, but failed to achieve statistical significance in primary and secondary endpoints. © 2010 Movement Disorder Society</div></front></TEI><istex><corpusName>wiley</corpusName><author><json:item><name>Karla Eggert MD</name><affiliations><json:string>German Competence Network on Parkinson's Disease, Department of Neurology, Philipps‐University Marburg, Marburg, Germany</json:string></affiliations></json:item><json:item><name>David Squillacote MD</name><affiliations><json:string>Eisai Global Clinical Development, Eisai Medical Research Inc., Woodcliff Lake, New Jersey, USA</json:string></affiliations></json:item><json:item><name>Paolo Barone MD</name><affiliations><json:string>Department of Neurological Sciences, University of Naples Federico II‐IDC Hermitage‐Capodimonte, Naples, Italy</json:string></affiliations></json:item><json:item><name>Richard Dodel MD</name><affiliations><json:string>Department of Neurology, Rheinische Friedrich‐Wilhelms‐University, Bonn, Germany</json:string></affiliations></json:item><json:item><name>Regina Katzenschlager MD</name><affiliations><json:string>Department of Neurology, Donauspital, Vienna, Austria</json:string></affiliations></json:item><json:item><name>Murat Emre MD</name><affiliations><json:string>Department of Neurology, Istanbul Medical School, Istanbul, Turkey</json:string></affiliations></json:item><json:item><name>Andrew J. Lees MD</name><affiliations><json:string>Reta Lila Weston Institute of Neurological Studies, University College London, London, United Kingdom</json:string></affiliations></json:item><json:item><name>Olivier Rascol MD, PhD</name><affiliations><json:string>Clinical Investigation Center, INSERM CIC9302, University Hospital Toulouse, Toulouse, France</json:string><json:string>Departments of Clinical Pharmacology and Neurosciences, INSERM UMR825, University Hospital Toulouse, Toulouse, France</json:string></affiliations></json:item><json:item><name>Werner Poewe MD</name><affiliations><json:string>Department of Neurology, Medical University Innsbruck, Innsbruck, Austria</json:string></affiliations></json:item><json:item><name>Eduardo Tolosa MD</name><affiliations><json:string>Neurology Service, Hospital Clinic, Universitat de Barcelona, CIBERNED, Barcelona, Spain</json:string></affiliations></json:item><json:item><name>Claudia Trenkwalder MD</name><affiliations><json:string>Paracelsus‐Elena Klinik, Kassel, Germany</json:string></affiliations></json:item><json:item><name>Marco Onofrj MD</name><affiliations><json:string>Clinica Neurologica, Università Chieti‐Pescara, Italy</json:string></affiliations></json:item><json:item><name>Fabrizio Stocchi MD, PhD</name><affiliations><json:string>Department of Neurology, IRCCS San Raffaele, Rome, Italy</json:string></affiliations></json:item><json:item><name>Giuseppe Nappi MD</name><affiliations><json:string>Chair of Neurology, University “La Sapienza,” Rome, Italy</json:string><json:string>IRCCS “C. Mondino Institute of Neurology” Foundation, Pavia, Italy</json:string></affiliations></json:item><json:item><name>Vladimir Kostic MD</name><affiliations><json:string>Institute of Neurology, Clinical Centre of Serbia, Belgrade, Serbia</json:string></affiliations></json:item><json:item><name>Jagoda Potic MD</name><affiliations><json:string>Clinic for Neurology and Psychiatry, Clinical Hospital Centre “Zvezdara,” Belgrade, Serbia</json:string></affiliations></json:item><json:item><name>Evzen Ruzicka MD, DSc</name><affiliations><json:string>Department of Neurology, Charles University in Prague, 1st Faculty of Medicine and General Teaching Hospital, Prague, Czech Republic</json:string></affiliations></json:item><json:item><name>Wolfgang Oertel MD</name><affiliations><json:string>German Competence Network on Parkinson's Disease, Department of Neurology, Philipps‐University Marburg, Marburg, Germany</json:string></affiliations></json:item></author><subject><json:item><lang><json:string>eng</json:string></lang><value>Parkinson's disease</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>motor fluctuations</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>dyskinesia</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>perampanel</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>AMPA receptor antagonist</value></json:item></subject><language><json:string>eng</json:string></language><abstract>Perampanel, a novel, noncompetitive, selective AMPA‐receptor antagonist demonstrated evidence of efficacy in reducing motor symptoms in animal models of Parkinson's disease (PD). We assessed the safety and efficacy of perampanel for treatment of “wearing off” motor fluctuations in patients with PD. Patients (N = 263) were randomly assigned to once‐daily add‐on 0.5, 1, or 2 mg of perampanel or placebo. The primary objective was to determine whether there was a dose‐response relationship for efficacy among the 3 perampanel doses and placebo. The primary efficacy endpoint for each treatment was measured as the least‐squares (LS) mean change from baseline to week 12 in percent “off” time reduction during the waking day, as recorded by patient diaries. The primary efficacy analysis was a 1‐sided Williams test for dose‐response trend at the 0.025 level of significance. At week 12, dose‐response trends, as determined by the Williams test, were not statistically significant for LS mean reduction in percent “off” time during the waking day (P = 0.061, with significance defined as P ≤ 0.025). The 2 higher perampanel doses (ITT population; n = 258) produced nonsignificant reductions from baseline to week 12 in percent “off” time during the waking day versus placebo (7.59%, P= 0.421 [1 mg], 8.60%, P = 0.257 [2 mg] versus 5.05% [placebo]; significance for pairwise comparisons defined as P ≤ 0.05). There were no significant changes in dyskinesia or cognitive function in any perampanel group versus placebo. Adverse events were similar across treatment groups. Perampanel treatment was well tolerated and safe, but failed to achieve statistical significance in primary and secondary endpoints. © 2010 Movement Disorder Society</abstract><qualityIndicators><score>8</score><pdfVersion>1.3</pdfVersion><pdfPageSize>612 x 810 pts</pdfPageSize><refBibsNative>true</refBibsNative><abstractCharCount>1736</abstractCharCount><pdfWordCount>5767</pdfWordCount><pdfCharCount>38876</pdfCharCount><pdfPageCount>10</pdfPageCount><abstractWordCount>267</abstractWordCount></qualityIndicators><title>Safety and efficacy of perampanel in advanced Parkinson's disease: A randomized, placebo‐controlled study</title><corporate><json:item><name></name></json:item></corporate><genre><json:string>Serial article</json:string></genre><host><volume>25</volume><pages><total>10</total><last>905</last><first>896</first></pages><issn><json:string>0885-3185</json:string></issn><issue>7</issue><subject><json:item><value>Research Article</value></json:item></subject><genre></genre><language><json:string>unknown</json:string></language><title>Movement Disorders</title><doi><json:string>10.1002/(ISSN)1531-8257</json:string></doi></host><publicationDate>2010</publicationDate><copyrightDate>2010</copyrightDate><doi><json:string>10.1002/mds.22974</json:string></doi><id>F3991B9F741986E5D89C72FDB4FA8C332024F02F</id><fulltext><json:item><original>true</original><mimetype>application/pdf</mimetype><extension>pdf</extension><uri>https://api.istex.fr/document/F3991B9F741986E5D89C72FDB4FA8C332024F02F/fulltext/pdf</uri></json:item><json:item><original>false</original><mimetype>application/zip</mimetype><extension>zip</extension><uri>https://api.istex.fr/document/F3991B9F741986E5D89C72FDB4FA8C332024F02F/fulltext/zip</uri></json:item><istex:fulltextTEI uri="https://api.istex.fr/document/F3991B9F741986E5D89C72FDB4FA8C332024F02F/fulltext/tei"><teiHeader type="text"><fileDesc><titleStmt><title level="a" type="main" xml:lang="en">Safety and efficacy of perampanel in advanced Parkinson's disease: A randomized, placebo‐controlled study</title></titleStmt><publicationStmt><authority>ISTEX</authority><publisher>Wiley Subscription Services, Inc., A Wiley Company</publisher><pubPlace>Hoboken</pubPlace><availability><p>Wiley Subscription Services, Inc., A Wiley Company</p></availability><date>2010</date></publicationStmt><notesStmt><note type="content">*Potential conflict of interest: This study and editorial support were sponsored by Eisai Co., Ltd. No compensation was provided to the authors for their work on this manuscript. All authors, except for Dr. Squillacote, received compensation from Eisai for their site's conduct of the study. Drs. Barone, Lees, and Oertel received honoraria from Eisai as members of the Advisory Board of this study. Dr. Rascol has received unrestricted scientific grant and honoraria from Eisai for his advice to the company on this project. Dr. Dodel received honoraria from Eisai for presenting the study at meetings. Drs. Katzenschlager, Poewe, Kostic, and Ruzicka received honoraria from Eisai for consulting in relation to this study. Dr. Emre has been on the Protocol Development and Advisory Committee for the study and received honoraria for his advice. Dr. Onofrj received honoraria from Eisai in his capacity as Principal Investigator.</note></notesStmt><sourceDesc><biblStruct type="inbook"><analytic><title level="a" type="main" xml:lang="en">Safety and efficacy of perampanel in advanced Parkinson's disease: A randomized, placebo‐controlled study</title><author><orgName>and in cooperation with the German Competence Network on Parkinson's Disease</orgName></author><author><persName><forename type="first">Karla</forename><surname>Eggert</surname><roleName type="degree">MD</roleName></persName><affiliation>German Competence Network on Parkinson's Disease, Department of Neurology, Philipps‐University Marburg, Marburg, Germany</affiliation></author><author><persName><forename type="first">David</forename><surname>Squillacote</surname><roleName type="degree">MD</roleName></persName><affiliation>Eisai Global Clinical Development, Eisai Medical Research Inc., Woodcliff Lake, New Jersey, USA</affiliation></author><author><persName><forename type="first">Paolo</forename><surname>Barone</surname><roleName type="degree">MD</roleName></persName><affiliation>Department of Neurological Sciences, University of Naples Federico II‐IDC Hermitage‐Capodimonte, Naples, Italy</affiliation></author><author><persName><forename type="first">Richard</forename><surname>Dodel</surname><roleName type="degree">MD</roleName></persName><affiliation>Department of Neurology, Rheinische Friedrich‐Wilhelms‐University, Bonn, Germany</affiliation></author><author><persName><forename type="first">Regina</forename><surname>Katzenschlager</surname><roleName type="degree">MD</roleName></persName><affiliation>Department of Neurology, Donauspital, Vienna, Austria</affiliation></author><author><persName><forename type="first">Murat</forename><surname>Emre</surname><roleName type="degree">MD</roleName></persName><affiliation>Department of Neurology, Istanbul Medical School, Istanbul, Turkey</affiliation></author><author><persName><forename type="first">Andrew J.</forename><surname>Lees</surname><roleName type="degree">MD</roleName></persName><affiliation>Reta Lila Weston Institute of Neurological Studies, University College London, London, United Kingdom</affiliation></author><author><persName><forename type="first">Olivier</forename><surname>Rascol</surname><roleName type="degree">MD, PhD</roleName></persName><affiliation>Clinical Investigation Center, INSERM CIC9302, University Hospital Toulouse, Toulouse, France</affiliation><affiliation>Departments of Clinical Pharmacology and Neurosciences, INSERM UMR825, University Hospital Toulouse, Toulouse, France</affiliation></author><author><persName><forename type="first">Werner</forename><surname>Poewe</surname><roleName type="degree">MD</roleName></persName><affiliation>Department of Neurology, Medical University Innsbruck, Innsbruck, Austria</affiliation></author><author><persName><forename type="first">Eduardo</forename><surname>Tolosa</surname><roleName type="degree">MD</roleName></persName><affiliation>Neurology Service, Hospital Clinic, Universitat de Barcelona, CIBERNED, Barcelona, Spain</affiliation></author><author><persName><forename type="first">Claudia</forename><surname>Trenkwalder</surname><roleName type="degree">MD</roleName></persName><affiliation>Paracelsus‐Elena Klinik, Kassel, Germany</affiliation></author><author><persName><forename type="first">Marco</forename><surname>Onofrj</surname><roleName type="degree">MD</roleName></persName><affiliation>Clinica Neurologica, Università Chieti‐Pescara, Italy</affiliation></author><author><persName><forename type="first">Fabrizio</forename><surname>Stocchi</surname><roleName type="degree">MD, PhD</roleName></persName><affiliation>Department of Neurology, IRCCS San Raffaele, Rome, Italy</affiliation></author><author><persName><forename type="first">Giuseppe</forename><surname>Nappi</surname><roleName type="degree">MD</roleName></persName><affiliation>Chair of Neurology, University “La Sapienza,” Rome, Italy</affiliation><affiliation>IRCCS “C. Mondino Institute of Neurology” Foundation, Pavia, Italy</affiliation></author><author><persName><forename type="first">Vladimir</forename><surname>Kostic</surname><roleName type="degree">MD</roleName></persName><affiliation>Institute of Neurology, Clinical Centre of Serbia, Belgrade, Serbia</affiliation></author><author><persName><forename type="first">Jagoda</forename><surname>Potic</surname><roleName type="degree">MD</roleName></persName><affiliation>Clinic for Neurology and Psychiatry, Clinical Hospital Centre “Zvezdara,” Belgrade, Serbia</affiliation></author><author><persName><forename type="first">Evzen</forename><surname>Ruzicka</surname><roleName type="degree">MD, DSc</roleName></persName><affiliation>Department of Neurology, Charles University in Prague, 1st Faculty of Medicine and General Teaching Hospital, Prague, Czech Republic</affiliation></author><author><persName><forename type="first">Wolfgang</forename><surname>Oertel</surname><roleName type="degree">MD</roleName></persName><note type="correspondence"><p>Correspondence: German Competence Network on Parkinson's Disease, Department of Neurology, Philipps‐University Marburg, Rudolf‐Bultmann‐Str. 8, D‐35033 Marburg, Germany</p></note><affiliation>German Competence Network on Parkinson's Disease, Department of Neurology, Philipps‐University Marburg, Marburg, Germany</affiliation></author></analytic><monogr><title level="j">Movement Disorders</title><title level="j" type="abbrev">Mov. Disord.</title><idno type="pISSN">0885-3185</idno><idno type="eISSN">1531-8257</idno><idno type="DOI">10.1002/(ISSN)1531-8257</idno><imprint><publisher>Wiley Subscription Services, Inc., A Wiley Company</publisher><pubPlace>Hoboken</pubPlace><date type="published" when="2010-05-15"></date><biblScope unit="vol">25</biblScope><biblScope unit="issue">7</biblScope><biblScope unit="page" from="896">896</biblScope><biblScope unit="page" to="905">905</biblScope></imprint></monogr><idno type="istex">F3991B9F741986E5D89C72FDB4FA8C332024F02F</idno><idno type="DOI">10.1002/mds.22974</idno><idno type="ArticleID">MDS22974</idno></biblStruct></sourceDesc></fileDesc><profileDesc><creation><date>2010</date></creation><langUsage><language ident="en">en</language></langUsage><abstract xml:lang="en"><p>Perampanel, a novel, noncompetitive, selective AMPA‐receptor antagonist demonstrated evidence of efficacy in reducing motor symptoms in animal models of Parkinson's disease (PD). We assessed the safety and efficacy of perampanel for treatment of “wearing off” motor fluctuations in patients with PD. Patients (N = 263) were randomly assigned to once‐daily add‐on 0.5, 1, or 2 mg of perampanel or placebo. The primary objective was to determine whether there was a dose‐response relationship for efficacy among the 3 perampanel doses and placebo. The primary efficacy endpoint for each treatment was measured as the least‐squares (LS) mean change from baseline to week 12 in percent “off” time reduction during the waking day, as recorded by patient diaries. The primary efficacy analysis was a 1‐sided Williams test for dose‐response trend at the 0.025 level of significance. At week 12, dose‐response trends, as determined by the Williams test, were not statistically significant for LS mean reduction in percent “off” time during the waking day (P = 0.061, with significance defined as P ≤ 0.025). The 2 higher perampanel doses (ITT population; n = 258) produced nonsignificant reductions from baseline to week 12 in percent “off” time during the waking day versus placebo (7.59%, P= 0.421 [1 mg], 8.60%, P = 0.257 [2 mg] versus 5.05% [placebo]; significance for pairwise comparisons defined as P ≤ 0.05). There were no significant changes in dyskinesia or cognitive function in any perampanel group versus placebo. Adverse events were similar across treatment groups. Perampanel treatment was well tolerated and safe, but failed to achieve statistical significance in primary and secondary endpoints. © 2010 Movement Disorder Society</p></abstract><textClass xml:lang="en"><keywords scheme="keyword"><list><head>Keywords</head><item><term>Parkinson's disease</term></item><item><term>motor fluctuations</term></item><item><term>dyskinesia</term></item><item><term>perampanel</term></item><item><term>AMPA receptor antagonist</term></item></list></keywords></textClass><textClass><keywords scheme="Journal Subject"><list><head>Article category</head><item><term>Research Article</term></item></list></keywords></textClass></profileDesc><revisionDesc><change when="2009-02-03">Received</change><change when="2009-11-20">Registration</change><change when="2010-05-15">Published</change></revisionDesc></teiHeader></istex:fulltextTEI><json:item><original>false</original><mimetype>text/plain</mimetype><extension>txt</extension><uri>https://api.istex.fr/document/F3991B9F741986E5D89C72FDB4FA8C332024F02F/fulltext/txt</uri></json:item></fulltext><metadata><istex:metadataXml wicri:clean="Wiley, elements deleted: body"><istex:xmlDeclaration>version="1.0" encoding="UTF-8" standalone="yes"</istex:xmlDeclaration><istex:document><component version="2.0" type="serialArticle" xml:lang="en"><header><publicationMeta level="product"><publisherInfo><publisherName>Wiley Subscription Services, Inc., A Wiley Company</publisherName><publisherLoc>Hoboken</publisherLoc></publisherInfo><doi registered="yes">10.1002/(ISSN)1531-8257</doi><issn type="print">0885-3185</issn><issn type="electronic">1531-8257</issn><idGroup><id type="product" value="MDS"></id></idGroup><titleGroup><title type="main" xml:lang="en" sort="MOVEMENT DISORDERS">Movement Disorders</title><title type="short">Mov. 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We assessed the safety and efficacy of perampanel for treatment of “wearing off” motor fluctuations in patients with PD. Patients (N = 263) were randomly assigned to once‐daily add‐on 0.5, 1, or 2 mg of perampanel or placebo. The primary objective was to determine whether there was a dose‐response relationship for efficacy among the 3 perampanel doses and placebo. The primary efficacy endpoint for each treatment was measured as the least‐squares (LS) mean change from baseline to week 12 in percent “off” time reduction during the waking day, as recorded by patient diaries. The primary efficacy analysis was a 1‐sided Williams test for dose‐response trend at the 0.025 level of significance. At week 12, dose‐response trends, as determined by the Williams test, were not statistically significant for LS mean reduction in percent “off” time during the waking day (<i>P</i> = 0.061, with significance defined as <i>P</i> ≤ 0.025). The 2 higher perampanel doses (ITT population; n = 258) produced nonsignificant reductions from baseline to week 12 in percent “off” time during the waking day versus placebo (7.59%, <i>P</i>= 0.421 [1 mg], 8.60%, <i>P</i> = 0.257 [2 mg] versus 5.05% [placebo]; significance for pairwise comparisons defined as <i>P</i> ≤ 0.05). There were no significant changes in dyskinesia or cognitive function in any perampanel group versus placebo. Adverse events were similar across treatment groups. Perampanel treatment was well tolerated and safe, but failed to achieve statistical significance in primary and secondary endpoints. © 2010 Movement Disorder Society</p></abstract></abstractGroup></contentMeta><noteGroup><note xml:id="fn7"><p>Potential conflict of interest: This study and editorial support were sponsored by Eisai Co., Ltd. No compensation was provided to the authors for their work on this manuscript. All authors, except for Dr. Squillacote, received compensation from Eisai for their site's conduct of the study. Drs. Barone, Lees, and Oertel received honoraria from Eisai as members of the Advisory Board of this study. Dr. Rascol has received unrestricted scientific grant and honoraria from Eisai for his advice to the company on this project. Dr. Dodel received honoraria from Eisai for presenting the study at meetings. Drs. Katzenschlager, Poewe, Kostic, and Ruzicka received honoraria from Eisai for consulting in relation to this study. Dr. Emre has been on the Protocol Development and Advisory Committee for the study and received honoraria for his advice. Dr. Onofrj received honoraria from Eisai in his capacity as Principal Investigator.</p></note></noteGroup></header></component></istex:document></istex:metadataXml><!--Version 0.6 générée le 3-12-2015--><mods version="3.6"><titleInfo lang="en"><title>Safety and efficacy of perampanel in advanced Parkinson's disease: A randomized, placebo‐controlled study</title></titleInfo><titleInfo type="abbreviated" lang="en"><title>Perampanel in Advanced Parkinson's Disease</title></titleInfo><titleInfo type="alternative" contentType="CDATA" lang="en"><title>Safety and efficacy of perampanel in advanced Parkinson's disease: A randomized, placebo‐controlled study</title></titleInfo><name type="personal"><namePart type="given">Karla</namePart><namePart type="family">Eggert</namePart><namePart type="termsOfAddress">MD</namePart><affiliation>German Competence Network on Parkinson's Disease, Department of Neurology, Philipps‐University Marburg, Marburg, Germany</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">David</namePart><namePart type="family">Squillacote</namePart><namePart type="termsOfAddress">MD</namePart><affiliation>Eisai Global Clinical Development, Eisai Medical Research Inc., Woodcliff Lake, New Jersey, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Paolo</namePart><namePart type="family">Barone</namePart><namePart type="termsOfAddress">MD</namePart><affiliation>Department of Neurological Sciences, University of Naples Federico II‐IDC Hermitage‐Capodimonte, Naples, Italy</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Richard</namePart><namePart type="family">Dodel</namePart><namePart type="termsOfAddress">MD</namePart><affiliation>Department of Neurology, Rheinische Friedrich‐Wilhelms‐University, Bonn, Germany</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Regina</namePart><namePart type="family">Katzenschlager</namePart><namePart type="termsOfAddress">MD</namePart><affiliation>Department of Neurology, Donauspital, Vienna, Austria</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Murat</namePart><namePart type="family">Emre</namePart><namePart type="termsOfAddress">MD</namePart><affiliation>Department of Neurology, Istanbul Medical School, Istanbul, Turkey</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Andrew J.</namePart><namePart type="family">Lees</namePart><namePart type="termsOfAddress">MD</namePart><affiliation>Reta Lila Weston Institute of Neurological Studies, University College London, London, United Kingdom</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Olivier</namePart><namePart type="family">Rascol</namePart><namePart type="termsOfAddress">MD, PhD</namePart><affiliation>Clinical Investigation Center, INSERM CIC9302, University Hospital Toulouse, Toulouse, France</affiliation><affiliation>Departments of Clinical Pharmacology and Neurosciences, INSERM UMR825, University Hospital Toulouse, Toulouse, France</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Werner</namePart><namePart type="family">Poewe</namePart><namePart type="termsOfAddress">MD</namePart><affiliation>Department of Neurology, Medical University Innsbruck, Innsbruck, Austria</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Eduardo</namePart><namePart type="family">Tolosa</namePart><namePart type="termsOfAddress">MD</namePart><affiliation>Neurology Service, Hospital Clinic, Universitat de Barcelona, CIBERNED, Barcelona, Spain</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Claudia</namePart><namePart type="family">Trenkwalder</namePart><namePart type="termsOfAddress">MD</namePart><affiliation>Paracelsus‐Elena Klinik, Kassel, Germany</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Marco</namePart><namePart type="family">Onofrj</namePart><namePart type="termsOfAddress">MD</namePart><affiliation>Clinica Neurologica, Università Chieti‐Pescara, Italy</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Fabrizio</namePart><namePart type="family">Stocchi</namePart><namePart type="termsOfAddress">MD, PhD</namePart><affiliation>Department of Neurology, IRCCS San Raffaele, Rome, Italy</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Giuseppe</namePart><namePart type="family">Nappi</namePart><namePart type="termsOfAddress">MD</namePart><affiliation>Chair of Neurology, University “La Sapienza,” Rome, Italy</affiliation><affiliation>IRCCS “C. Mondino Institute of Neurology” Foundation, Pavia, Italy</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Vladimir</namePart><namePart type="family">Kostic</namePart><namePart type="termsOfAddress">MD</namePart><affiliation>Institute of Neurology, Clinical Centre of Serbia, Belgrade, Serbia</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Jagoda</namePart><namePart type="family">Potic</namePart><namePart type="termsOfAddress">MD</namePart><affiliation>Clinic for Neurology and Psychiatry, Clinical Hospital Centre “Zvezdara,” Belgrade, Serbia</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Evzen</namePart><namePart type="family">Ruzicka</namePart><namePart type="termsOfAddress">MD, DSc</namePart><affiliation>Department of Neurology, Charles University in Prague, 1st Faculty of Medicine and General Teaching Hospital, Prague, Czech Republic</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Wolfgang</namePart><namePart type="family">Oertel</namePart><namePart type="termsOfAddress">MD</namePart><affiliation>German Competence Network on Parkinson's Disease, Department of Neurology, Philipps‐University Marburg, Marburg, Germany</affiliation><description>Correspondence: German Competence Network on Parkinson's Disease, Department of Neurology, Philipps‐University Marburg, Rudolf‐Bultmann‐Str. 8, D‐35033 Marburg, Germany</description><role><roleTerm type="text">author</roleTerm></role></name><name type="corporate"><namePart>and in cooperation with the German Competence Network on Parkinson's Disease</namePart><description>German Competence Network on Parkinson's Disease, Department of Neurology, Philipps‐University Marburg, Marburg, GermanyEisai Global Clinical Development, Eisai Medical Research Inc., Woodcliff Lake, New Jersey, USADepartment of Neurological Sciences, University of Naples Federico II‐IDC Hermitage‐Capodimonte, Naples, ItalyDepartment of Neurology, Rheinische Friedrich‐Wilhelms‐University, Bonn, GermanyDepartment of Neurology, Donauspital, Vienna, AustriaDepartment of Neurology, Istanbul Medical School, Istanbul, TurkeyReta Lila Weston Institute of Neurological Studies, University College London, London, United KingdomClinical Investigation Center, INSERM CIC9302, University Hospital Toulouse, Toulouse, FranceDepartments of Clinical Pharmacology and Neurosciences, INSERM UMR825, University Hospital Toulouse, Toulouse, FranceDepartment of Neurology, Medical University Innsbruck, Innsbruck, AustriaNeurology Service, Hospital Clinic, Universitat de Barcelona, CIBERNED, Barcelona, SpainParacelsus‐Elena Klinik, Kassel, GermanyClinica Neurologica, Università Chieti‐Pescara, ItalyDepartment of Neurology, IRCCS San Raffaele, Rome, ItalyChair of Neurology, University “La Sapienza,” Rome, ItalyIRCCS “C. Mondino Institute of Neurology” Foundation, Pavia, ItalyInstitute of Neurology, Clinical Centre of Serbia, Belgrade, SerbiaClinic for Neurology and Psychiatry, Clinical Hospital Centre “Zvezdara,” Belgrade, SerbiaDepartment of Neurology, Charles University in Prague, 1st Faculty of Medicine and General Teaching Hospital, Prague, Czech Republic</description></name><typeOfResource>text</typeOfResource><genre authority="originalCategForm">article</genre><originInfo><publisher>Wiley Subscription Services, Inc., A Wiley Company</publisher><place><placeTerm type="text">Hoboken</placeTerm></place><dateIssued encoding="w3cdtf">2010-05-15</dateIssued><dateCaptured encoding="w3cdtf">2009-02-03</dateCaptured><dateValid encoding="w3cdtf">2009-11-20</dateValid><copyrightDate encoding="w3cdtf">2010</copyrightDate></originInfo><language><languageTerm type="code" authority="rfc3066">en</languageTerm><languageTerm type="code" authority="iso639-2b">eng</languageTerm></language><physicalDescription><internetMediaType>text/html</internetMediaType><extent unit="figures">1</extent><extent unit="tables">4</extent><extent unit="references">27</extent><extent unit="words">8301</extent></physicalDescription><abstract lang="en">Perampanel, a novel, noncompetitive, selective AMPA‐receptor antagonist demonstrated evidence of efficacy in reducing motor symptoms in animal models of Parkinson's disease (PD). We assessed the safety and efficacy of perampanel for treatment of “wearing off” motor fluctuations in patients with PD. Patients (N = 263) were randomly assigned to once‐daily add‐on 0.5, 1, or 2 mg of perampanel or placebo. The primary objective was to determine whether there was a dose‐response relationship for efficacy among the 3 perampanel doses and placebo. The primary efficacy endpoint for each treatment was measured as the least‐squares (LS) mean change from baseline to week 12 in percent “off” time reduction during the waking day, as recorded by patient diaries. The primary efficacy analysis was a 1‐sided Williams test for dose‐response trend at the 0.025 level of significance. At week 12, dose‐response trends, as determined by the Williams test, were not statistically significant for LS mean reduction in percent “off” time during the waking day (P = 0.061, with significance defined as P ≤ 0.025). The 2 higher perampanel doses (ITT population; n = 258) produced nonsignificant reductions from baseline to week 12 in percent “off” time during the waking day versus placebo (7.59%, P= 0.421 [1 mg], 8.60%, P = 0.257 [2 mg] versus 5.05% [placebo]; significance for pairwise comparisons defined as P ≤ 0.05). There were no significant changes in dyskinesia or cognitive function in any perampanel group versus placebo. Adverse events were similar across treatment groups. Perampanel treatment was well tolerated and safe, but failed to achieve statistical significance in primary and secondary endpoints. © 2010 Movement Disorder Society</abstract><note type="content">*Potential conflict of interest: This study and editorial support were sponsored by Eisai Co., Ltd. No compensation was provided to the authors for their work on this manuscript. All authors, except for Dr. Squillacote, received compensation from Eisai for their site's conduct of the study. Drs. Barone, Lees, and Oertel received honoraria from Eisai as members of the Advisory Board of this study. Dr. Rascol has received unrestricted scientific grant and honoraria from Eisai for his advice to the company on this project. Dr. Dodel received honoraria from Eisai for presenting the study at meetings. Drs. Katzenschlager, Poewe, Kostic, and Ruzicka received honoraria from Eisai for consulting in relation to this study. Dr. Emre has been on the Protocol Development and Advisory Committee for the study and received honoraria for his advice. Dr. Onofrj received honoraria from Eisai in his capacity as Principal Investigator.</note><subject lang="en"><genre>Keywords</genre><topic>Parkinson's disease</topic><topic>motor fluctuations</topic><topic>dyskinesia</topic><topic>perampanel</topic><topic>AMPA receptor antagonist</topic></subject><relatedItem type="host"><titleInfo><title>Movement Disorders</title></titleInfo><titleInfo type="abbreviated"><title>Mov. Disord.</title></titleInfo><subject><genre>article category</genre><topic>Research Article</topic></subject><identifier type="ISSN">0885-3185</identifier><identifier type="eISSN">1531-8257</identifier><identifier type="DOI">10.1002/(ISSN)1531-8257</identifier><identifier type="PublisherID">MDS</identifier><part><date>2010</date><detail type="volume"><caption>vol.</caption><number>25</number></detail><detail type="issue"><caption>no.</caption><number>7</number></detail><extent unit="pages"><start>896</start><end>905</end><total>10</total></extent></part></relatedItem><identifier type="istex">F3991B9F741986E5D89C72FDB4FA8C332024F02F</identifier><identifier type="DOI">10.1002/mds.22974</identifier><identifier type="ArticleID">MDS22974</identifier><accessCondition type="use and reproduction" contentType="copyright">Copyright © 2010 Movement Disorder Society</accessCondition><recordInfo><recordOrigin>Wiley Subscription Services, Inc., A Wiley Company</recordOrigin><recordContentSource>WILEY</recordContentSource></recordInfo></mods></metadata><serie></serie></istex></record>Pour manipuler ce document sous Unix (Dilib)
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