AFQ056 in Parkinson patients with levodopa‐induced dyskinesia: 13‐week, randomized, dose‐finding study
Identifieur interne : 001C14 ( Istex/Corpus ); précédent : 001C13; suivant : 001C15AFQ056 in Parkinson patients with levodopa‐induced dyskinesia: 13‐week, randomized, dose‐finding study
Auteurs : Fabrizio Stocchi ; Olivier Rascol ; Alain Destee ; Nobutaka Hattori ; Robert A. Hauser ; Anthony E. Lang ; Werner Poewe ; Mark Stacy ; Eduardo Tolosa ; Haitao Gao ; Jennifer Nagel ; Martin Merschhemke ; Ana Graf ; Christopher Kenney ; Claudia TrenkwalderSource :
- Movement Disorders [ 0885-3185 ] ; 2013-11.
Abstract
AFQ056 is a novel, selective metabotropic glutamate receptor 5 antagonist. This was a 13‐week, double‐blind, placebo‐controlled study. Patients with Parkinson's disease and moderate‐to‐severe levodopa (l‐dopa)‐induced dyskinesia who were receiving stable l‐dopa/anti‐parkinsonian treatment and were not currently receiving amantadine were randomized to receive either AFQ056 (at doses of 20, 50, 100, 150, or 200 mg daily) or placebo (1:1:1:1:2:3 ratio) for 12 weeks. The primary outcome was the modified Abnormal Involuntary Movements Scale. Secondary outcomes included the 26‐item Parkinson's Disease Dyskinesia Scale, the Patient's/Clinician's Global Impression of Change, and the Unified Parkinson's Disease Rating Scale parts III (motor evaluation) and IV (severity of motor complications). Safety was assessed. In total, 98 of 133 (73.7%) AFQ056‐treated patients and 47 of 64 (73.4%) patients in the placebo group completed the study. Baseline characteristics were comparable. Patients randomized to AFQ056 200 mg daily administered in 2 doses demonstrated significant improvements at Week 12 on the modified Abnormal Involuntary Movements Scale compared with placebo (difference, −2.8; 95% confidence interval [CI], −5.2, −0.4; P = 0.007). Based on final actual doses, there was a dose‐response relationship on the modified Abnormal Involuntary Movements Scale, with 200 mg daily demonstrating the most robust effect (difference, −3.6; 95% CI, −7.0, −0.3; P = 0.012). Improvements in dyskinesia were supported by change on Unified Parkinson's Disease Rating Scale part IV item 32 (50 mg daily: difference, −0.7; 95% CI, −1.1, −0.2; P = 0.003; 200 mg daily: difference, −0.5; 95% CI, −0.8, −0.1; P = 0.005). No significant changes were observed on the 26‐item Parkinson's Disease Dyskinesia Scale, the Unified Parkinson's Disease Rating Scale part IV item 33 or items 32 and 33, or the Patient's/Clinician's Global Impression of Change. Unified Parkinson's Disease Rating Scale part III scores were not significantly changed, indicating no worsening of motor symptoms. The most common adverse events (with incidence greater with AFQ056 than with placebo) were dizziness, hallucination, fatigue, nasopharyngitis, diarrhea, and insomnia. AFQ056 demonstrated anti‐dyskinetic efficacy in this population without worsening underlying motor symptoms. These results will guide dose selection for future clinical trials. © 2013 International Parkinson and Movement Disorder Society
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DOI: 10.1002/mds.25561
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<record><TEI wicri:istexFullTextTei="biblStruct"><teiHeader><fileDesc><titleStmt><title xml:lang="en">AFQ056 in Parkinson patients with levodopa‐induced dyskinesia: 13‐week, randomized, dose‐finding study</title><author><name sortKey="Stocchi, Fabrizio" sort="Stocchi, Fabrizio" uniqKey="Stocchi F" first="Fabrizio" last="Stocchi">Fabrizio Stocchi</name><affiliation><mods:affiliation>Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele Pisana, Rome, Italy</mods:affiliation></affiliation><affiliation><mods:affiliation>E-mail: fabrizio.stocchi@fastwebnet.it</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>Institut National de la Santé et de la Recherche Médicale (INSERM) CIC9302‐UMR825 and Departments of Neurosciences and Clinical Pharmacology, Toulouse University Hospital and University of Toulouse III, Toulouse, France</mods:affiliation></affiliation></author><author><name sortKey="Destee, Alain" sort="Destee, Alain" uniqKey="Destee A" first="Alain" last="Destee">Alain Destee</name><affiliation><mods:affiliation>Lille North of France University, Lille University Hospital, Movement Disorders Unit, INSERM U837, Lille, France</mods:affiliation></affiliation></author><author><name sortKey="Hattori, Nobutaka" sort="Hattori, Nobutaka" uniqKey="Hattori N" first="Nobutaka" last="Hattori">Nobutaka Hattori</name><affiliation><mods:affiliation>Department of Neurology, Juntendo University School of Medicine, Tokyo, Japan</mods:affiliation></affiliation></author><author><name sortKey="Hauser, Robert A" sort="Hauser, Robert A" uniqKey="Hauser R" first="Robert A." last="Hauser">Robert A. Hauser</name><affiliation><mods:affiliation>Department of Neurology, University of South Florida, Florida, Tampa, USA</mods:affiliation></affiliation></author><author><name sortKey="Lang, Anthony E" sort="Lang, Anthony E" uniqKey="Lang A" first="Anthony E." last="Lang">Anthony E. Lang</name><affiliation><mods:affiliation>Edmond J. Safra Program in Parkinson's Disease, Toronto Western Hospital, University of Toronto, Ontario, Toronto, Canada</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 of Innsbruck, Innsbruck, Austria</mods:affiliation></affiliation></author><author><name sortKey="Stacy, Mark" sort="Stacy, Mark" uniqKey="Stacy M" first="Mark" last="Stacy">Mark Stacy</name><affiliation><mods:affiliation>Department of Neurology, School of Medicine, Duke University Medical Center, North Carolina, Durham, USA</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, Barcelona, Spain; Centro de Investigación Biomédica en Red Enfermedades Neurodegenerativas (CIBERNED), Barcelona, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain</mods:affiliation></affiliation></author><author><name sortKey="Gao, Haitao" sort="Gao, Haitao" uniqKey="Gao H" first="Haitao" last="Gao">Haitao Gao</name><affiliation><mods:affiliation>Novartis Pharmaceuticals Corporation, New Jersey, East Hanover, USA</mods:affiliation></affiliation></author><author><name sortKey="Nagel, Jennifer" sort="Nagel, Jennifer" uniqKey="Nagel J" first="Jennifer" last="Nagel">Jennifer Nagel</name><affiliation><mods:affiliation>Novartis Pharma AG, Basel, Switzerland</mods:affiliation></affiliation></author><author><name sortKey="Merschhemke, Martin" sort="Merschhemke, Martin" uniqKey="Merschhemke M" first="Martin" last="Merschhemke">Martin Merschhemke</name><affiliation><mods:affiliation>Novartis Pharma AG, Basel, Switzerland</mods:affiliation></affiliation></author><author><name sortKey="Graf, Ana" sort="Graf, Ana" uniqKey="Graf A" first="Ana" last="Graf">Ana Graf</name><affiliation><mods:affiliation>Novartis Pharma AG, Basel, Switzerland</mods:affiliation></affiliation></author><author><name sortKey="Kenney, Christopher" sort="Kenney, Christopher" uniqKey="Kenney C" first="Christopher" last="Kenney">Christopher Kenney</name><affiliation><mods:affiliation>Novartis Pharmaceuticals Corporation, New Jersey, East Hanover, USA</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, Department of Neurosurgery, University Medical Center of Goettingen, Goettingen, Germany</mods:affiliation></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">ISTEX</idno><idno type="RBID">ISTEX:9A0BBD00C61270CF3E504E6B62F0E37B9F2B3155</idno><date when="2013" year="2013">2013</date><idno type="doi">10.1002/mds.25561</idno><idno type="url">https://api-v5.istex.fr/document/9A0BBD00C61270CF3E504E6B62F0E37B9F2B3155/fulltext/pdf</idno><idno type="wicri:Area/Istex/Corpus">001C14</idno><idno type="wicri:explorRef" wicri:stream="Istex" wicri:step="Corpus" wicri:corpus="ISTEX">001C14</idno></publicationStmt><sourceDesc><biblStruct><analytic><title level="a" type="main" xml:lang="en">AFQ056 in Parkinson patients with levodopa‐induced dyskinesia: 13‐week, randomized, dose‐finding study</title><author><name sortKey="Stocchi, Fabrizio" sort="Stocchi, Fabrizio" uniqKey="Stocchi F" first="Fabrizio" last="Stocchi">Fabrizio Stocchi</name><affiliation><mods:affiliation>Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele Pisana, Rome, Italy</mods:affiliation></affiliation><affiliation><mods:affiliation>E-mail: fabrizio.stocchi@fastwebnet.it</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>Institut National de la Santé et de la Recherche Médicale (INSERM) CIC9302‐UMR825 and Departments of Neurosciences and Clinical Pharmacology, Toulouse University Hospital and University of Toulouse III, Toulouse, France</mods:affiliation></affiliation></author><author><name sortKey="Destee, Alain" sort="Destee, Alain" uniqKey="Destee A" first="Alain" last="Destee">Alain Destee</name><affiliation><mods:affiliation>Lille North of France University, Lille University Hospital, Movement Disorders Unit, INSERM U837, Lille, France</mods:affiliation></affiliation></author><author><name sortKey="Hattori, Nobutaka" sort="Hattori, Nobutaka" uniqKey="Hattori N" first="Nobutaka" last="Hattori">Nobutaka Hattori</name><affiliation><mods:affiliation>Department of Neurology, Juntendo University School of Medicine, Tokyo, Japan</mods:affiliation></affiliation></author><author><name sortKey="Hauser, Robert A" sort="Hauser, Robert A" uniqKey="Hauser R" first="Robert A." last="Hauser">Robert A. Hauser</name><affiliation><mods:affiliation>Department of Neurology, University of South Florida, Florida, Tampa, USA</mods:affiliation></affiliation></author><author><name sortKey="Lang, Anthony E" sort="Lang, Anthony E" uniqKey="Lang A" first="Anthony E." last="Lang">Anthony E. Lang</name><affiliation><mods:affiliation>Edmond J. Safra Program in Parkinson's Disease, Toronto Western Hospital, University of Toronto, Ontario, Toronto, Canada</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 of Innsbruck, Innsbruck, Austria</mods:affiliation></affiliation></author><author><name sortKey="Stacy, Mark" sort="Stacy, Mark" uniqKey="Stacy M" first="Mark" last="Stacy">Mark Stacy</name><affiliation><mods:affiliation>Department of Neurology, School of Medicine, Duke University Medical Center, North Carolina, Durham, USA</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, Barcelona, Spain; Centro de Investigación Biomédica en Red Enfermedades Neurodegenerativas (CIBERNED), Barcelona, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain</mods:affiliation></affiliation></author><author><name sortKey="Gao, Haitao" sort="Gao, Haitao" uniqKey="Gao H" first="Haitao" last="Gao">Haitao Gao</name><affiliation><mods:affiliation>Novartis Pharmaceuticals Corporation, New Jersey, East Hanover, USA</mods:affiliation></affiliation></author><author><name sortKey="Nagel, Jennifer" sort="Nagel, Jennifer" uniqKey="Nagel J" first="Jennifer" last="Nagel">Jennifer Nagel</name><affiliation><mods:affiliation>Novartis Pharma AG, Basel, Switzerland</mods:affiliation></affiliation></author><author><name sortKey="Merschhemke, Martin" sort="Merschhemke, Martin" uniqKey="Merschhemke M" first="Martin" last="Merschhemke">Martin Merschhemke</name><affiliation><mods:affiliation>Novartis Pharma AG, Basel, Switzerland</mods:affiliation></affiliation></author><author><name sortKey="Graf, Ana" sort="Graf, Ana" uniqKey="Graf A" first="Ana" last="Graf">Ana Graf</name><affiliation><mods:affiliation>Novartis Pharma AG, Basel, Switzerland</mods:affiliation></affiliation></author><author><name sortKey="Kenney, Christopher" sort="Kenney, Christopher" uniqKey="Kenney C" first="Christopher" last="Kenney">Christopher Kenney</name><affiliation><mods:affiliation>Novartis Pharmaceuticals Corporation, New Jersey, East Hanover, USA</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, Department of Neurosurgery, University Medical Center of Goettingen, Goettingen, 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>Blackwell Publishing Ltd</publisher><date type="published" when="2013-11">2013-11</date><biblScope unit="volume">28</biblScope><biblScope unit="issue">13</biblScope><biblScope unit="page" from="1838">1838</biblScope><biblScope unit="page" to="1846">1846</biblScope></imprint><idno type="ISSN">0885-3185</idno></series><idno type="istex">9A0BBD00C61270CF3E504E6B62F0E37B9F2B3155</idno><idno type="DOI">10.1002/mds.25561</idno><idno type="ArticleID">MDS25561</idno></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0885-3185</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract">AFQ056 is a novel, selective metabotropic glutamate receptor 5 antagonist. This was a 13‐week, double‐blind, placebo‐controlled study. Patients with Parkinson's disease and moderate‐to‐severe levodopa (l‐dopa)‐induced dyskinesia who were receiving stable l‐dopa/anti‐parkinsonian treatment and were not currently receiving amantadine were randomized to receive either AFQ056 (at doses of 20, 50, 100, 150, or 200 mg daily) or placebo (1:1:1:1:2:3 ratio) for 12 weeks. The primary outcome was the modified Abnormal Involuntary Movements Scale. Secondary outcomes included the 26‐item Parkinson's Disease Dyskinesia Scale, the Patient's/Clinician's Global Impression of Change, and the Unified Parkinson's Disease Rating Scale parts III (motor evaluation) and IV (severity of motor complications). Safety was assessed. In total, 98 of 133 (73.7%) AFQ056‐treated patients and 47 of 64 (73.4%) patients in the placebo group completed the study. Baseline characteristics were comparable. Patients randomized to AFQ056 200 mg daily administered in 2 doses demonstrated significant improvements at Week 12 on the modified Abnormal Involuntary Movements Scale compared with placebo (difference, −2.8; 95% confidence interval [CI], −5.2, −0.4; P = 0.007). Based on final actual doses, there was a dose‐response relationship on the modified Abnormal Involuntary Movements Scale, with 200 mg daily demonstrating the most robust effect (difference, −3.6; 95% CI, −7.0, −0.3; P = 0.012). Improvements in dyskinesia were supported by change on Unified Parkinson's Disease Rating Scale part IV item 32 (50 mg daily: difference, −0.7; 95% CI, −1.1, −0.2; P = 0.003; 200 mg daily: difference, −0.5; 95% CI, −0.8, −0.1; P = 0.005). No significant changes were observed on the 26‐item Parkinson's Disease Dyskinesia Scale, the Unified Parkinson's Disease Rating Scale part IV item 33 or items 32 and 33, or the Patient's/Clinician's Global Impression of Change. Unified Parkinson's Disease Rating Scale part III scores were not significantly changed, indicating no worsening of motor symptoms. The most common adverse events (with incidence greater with AFQ056 than with placebo) were dizziness, hallucination, fatigue, nasopharyngitis, diarrhea, and insomnia. AFQ056 demonstrated anti‐dyskinetic efficacy in this population without worsening underlying motor symptoms. These results will guide dose selection for future clinical trials. © 2013 International Parkinson and Movement Disorder Society</div></front></TEI><istex><corpusName>wiley</corpusName><author><json:item><name>Fabrizio Stocchi MD</name><affiliations><json:string>Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele Pisana, Rome, Italy</json:string><json:string>E-mail: fabrizio.stocchi@fastwebnet.it</json:string></affiliations></json:item><json:item><name>Olivier Rascol MD, PhD</name><affiliations><json:string>Institut National de la Santé et de la Recherche Médicale (INSERM) CIC9302‐UMR825 and Departments of Neurosciences and Clinical Pharmacology, Toulouse University Hospital and University of Toulouse III, Toulouse, France</json:string></affiliations></json:item><json:item><name>Alain Destee MD</name><affiliations><json:string>Lille North of France University, Lille University Hospital, Movement Disorders Unit, INSERM U837, Lille, France</json:string></affiliations></json:item><json:item><name>Nobutaka Hattori MD</name><affiliations><json:string>Department of Neurology, Juntendo University School of Medicine, Tokyo, Japan</json:string></affiliations></json:item><json:item><name>Robert A. Hauser MD</name><affiliations><json:string>Department of Neurology, University of South Florida, Florida, Tampa, USA</json:string></affiliations></json:item><json:item><name>Anthony E. Lang MD</name><affiliations><json:string>Edmond J. Safra Program in Parkinson's Disease, Toronto Western Hospital, University of Toronto, Ontario, Toronto, Canada</json:string></affiliations></json:item><json:item><name>Werner Poewe MD</name><affiliations><json:string>Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria</json:string></affiliations></json:item><json:item><name>Mark Stacy MD</name><affiliations><json:string>Department of Neurology, School of Medicine, Duke University Medical Center, North Carolina, Durham, USA</json:string></affiliations></json:item><json:item><name>Eduardo Tolosa MD</name><affiliations><json:string>Neurology Service, Hospital Clinic, Barcelona, Spain; Centro de Investigación Biomédica en Red Enfermedades Neurodegenerativas (CIBERNED), Barcelona, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain</json:string></affiliations></json:item><json:item><name>Haitao Gao PhD</name><affiliations><json:string>Novartis Pharmaceuticals Corporation, New Jersey, East Hanover, USA</json:string></affiliations></json:item><json:item><name>Jennifer Nagel PhD</name><affiliations><json:string>Novartis Pharma AG, Basel, Switzerland</json:string></affiliations></json:item><json:item><name>Martin Merschhemke MD</name><affiliations><json:string>Novartis Pharma AG, Basel, Switzerland</json:string></affiliations></json:item><json:item><name>Ana Graf MD</name><affiliations><json:string>Novartis Pharma AG, Basel, Switzerland</json:string></affiliations></json:item><json:item><name>Christopher Kenney MD</name><affiliations><json:string>Novartis Pharmaceuticals Corporation, New Jersey, East Hanover, USA</json:string></affiliations></json:item><json:item><name>Claudia Trenkwalder MD</name><affiliations><json:string>Paracelsus‐Elena‐Klinik, Kassel, Department of Neurosurgery, University Medical Center of Goettingen, Goettingen, 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>levodopa (l‐dopa)</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>glutamate antagonists</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>AFQ056</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>dyskinesias</value></json:item></subject><articleId><json:string>MDS25561</json:string></articleId><language><json:string>eng</json:string></language><originalGenre><json:string>article</json:string></originalGenre><abstract>AFQ056 is a novel, selective metabotropic glutamate receptor 5 antagonist. This was a 13‐week, double‐blind, placebo‐controlled study. Patients with Parkinson's disease and moderate‐to‐severe levodopa (l‐dopa)‐induced dyskinesia who were receiving stable l‐dopa/anti‐parkinsonian treatment and were not currently receiving amantadine were randomized to receive either AFQ056 (at doses of 20, 50, 100, 150, or 200 mg daily) or placebo (1:1:1:1:2:3 ratio) for 12 weeks. The primary outcome was the modified Abnormal Involuntary Movements Scale. Secondary outcomes included the 26‐item Parkinson's Disease Dyskinesia Scale, the Patient's/Clinician's Global Impression of Change, and the Unified Parkinson's Disease Rating Scale parts III (motor evaluation) and IV (severity of motor complications). Safety was assessed. In total, 98 of 133 (73.7%) AFQ056‐treated patients and 47 of 64 (73.4%) patients in the placebo group completed the study. Baseline characteristics were comparable. Patients randomized to AFQ056 200 mg daily administered in 2 doses demonstrated significant improvements at Week 12 on the modified Abnormal Involuntary Movements Scale compared with placebo (difference, −2.8; 95% confidence interval [CI], −5.2, −0.4; P = 0.007). Based on final actual doses, there was a dose‐response relationship on the modified Abnormal Involuntary Movements Scale, with 200 mg daily demonstrating the most robust effect (difference, −3.6; 95% CI, −7.0, −0.3; P = 0.012). Improvements in dyskinesia were supported by change on Unified Parkinson's Disease Rating Scale part IV item 32 (50 mg daily: difference, −0.7; 95% CI, −1.1, −0.2; P = 0.003; 200 mg daily: difference, −0.5; 95% CI, −0.8, −0.1; P = 0.005). No significant changes were observed on the 26‐item Parkinson's Disease Dyskinesia Scale, the Unified Parkinson's Disease Rating Scale part IV item 33 or items 32 and 33, or the Patient's/Clinician's Global Impression of Change. Unified Parkinson's Disease Rating Scale part III scores were not significantly changed, indicating no worsening of motor symptoms. The most common adverse events (with incidence greater with AFQ056 than with placebo) were dizziness, hallucination, fatigue, nasopharyngitis, diarrhea, and insomnia. AFQ056 demonstrated anti‐dyskinetic efficacy in this population without worsening underlying motor symptoms. These results will guide dose selection for future clinical trials. © 2013 International Parkinson and Movement Disorder Society</abstract><qualityIndicators><score>8</score><pdfVersion>1.3</pdfVersion><pdfPageSize>612 x 809.972 pts</pdfPageSize><refBibsNative>true</refBibsNative><abstractCharCount>2479</abstractCharCount><pdfWordCount>5555</pdfWordCount><pdfCharCount>36236</pdfCharCount><pdfPageCount>9</pdfPageCount><abstractWordCount>341</abstractWordCount></qualityIndicators><title>AFQ056 in Parkinson patients with levodopa‐induced dyskinesia: 13‐week, randomized, dose‐finding study</title><genre><json:string>article</json:string></genre><host><title>Movement Disorders</title><language><json:string>unknown</json:string></language><doi><json:string>10.1002/(ISSN)1531-8257</json:string></doi><issn><json:string>0885-3185</json:string></issn><eissn><json:string>1531-8257</json:string></eissn><publisherId><json:string>MDS</json:string></publisherId><volume>28</volume><issue>13</issue><pages><first>1838</first><last>1846</last><total>9</total></pages><genre><json:string>journal</json:string></genre><subject><json:item><value>Research Article</value></json:item></subject></host><categories><wos><json:string>science</json:string><json:string>clinical neurology</json:string></wos><scienceMetrix><json:string>health sciences</json:string><json:string>clinical medicine</json:string><json:string>neurology & neurosurgery</json:string></scienceMetrix></categories><publicationDate>2013</publicationDate><copyrightDate>2013</copyrightDate><doi><json:string>10.1002/mds.25561</json:string></doi><id>9A0BBD00C61270CF3E504E6B62F0E37B9F2B3155</id><fulltext><json:item><extension>pdf</extension><original>true</original><mimetype>application/pdf</mimetype><uri>https://api-v5.istex.fr/document/9A0BBD00C61270CF3E504E6B62F0E37B9F2B3155/fulltext/pdf</uri></json:item><json:item><extension>zip</extension><original>false</original><mimetype>application/zip</mimetype><uri>https://api-v5.istex.fr/document/9A0BBD00C61270CF3E504E6B62F0E37B9F2B3155/fulltext/zip</uri></json:item><istex:fulltextTEI uri="https://api-v5.istex.fr/document/9A0BBD00C61270CF3E504E6B62F0E37B9F2B3155/fulltext/tei"><teiHeader><fileDesc><titleStmt><title level="a" type="main" xml:lang="en">AFQ056 in Parkinson patients with levodopa‐induced dyskinesia: 13‐week, randomized, dose‐finding study</title></titleStmt><publicationStmt><authority>ISTEX</authority><publisher>Blackwell Publishing Ltd</publisher><availability><p>© 2013 Movement Disorder Society© 2013 Movement Disorder Society</p></availability><date>2013-05-27</date></publicationStmt><notesStmt><note>Novartis Pharma AG (Basel, Switzerland) - No. NCT00986414;</note></notesStmt><sourceDesc><biblStruct type="inbook"><analytic><title level="a" type="main" xml:lang="en">AFQ056 in Parkinson patients with levodopa‐induced dyskinesia: 13‐week, randomized, dose‐finding study</title><author xml:id="author-1"><persName><forename type="first">Fabrizio</forename><surname>Stocchi</surname></persName><roleName type="degree">MD</roleName><email>fabrizio.stocchi@fastwebnet.it</email><affiliation>Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele Pisana, Rome, Italy</affiliation></author><author xml:id="author-2"><persName><forename type="first">Olivier</forename><surname>Rascol</surname></persName><roleName type="degree">MD, PhD</roleName><affiliation>Institut National de la Santé et de la Recherche Médicale (INSERM) CIC9302‐UMR825 and Departments of Neurosciences and Clinical Pharmacology, Toulouse University Hospital and University of Toulouse III, Toulouse, France</affiliation></author><author xml:id="author-3"><persName><forename type="first">Alain</forename><surname>Destee</surname></persName><roleName type="degree">MD</roleName><affiliation>Lille North of France University, Lille University Hospital, Movement Disorders Unit, INSERM U837, Lille, France</affiliation></author><author xml:id="author-4"><persName><forename type="first">Nobutaka</forename><surname>Hattori</surname></persName><roleName type="degree">MD</roleName><affiliation>Department of Neurology, Juntendo University School of Medicine, Tokyo, Japan</affiliation></author><author xml:id="author-5"><persName><forename type="first">Robert A.</forename><surname>Hauser</surname></persName><roleName type="degree">MD</roleName><affiliation>Department of Neurology, University of South Florida, Florida, Tampa, USA</affiliation></author><author xml:id="author-6"><persName><forename type="first">Anthony E.</forename><surname>Lang</surname></persName><roleName type="degree">MD</roleName><affiliation>Edmond J. Safra Program in Parkinson's Disease, Toronto Western Hospital, University of Toronto, Ontario, Toronto, Canada</affiliation></author><author xml:id="author-7"><persName><forename type="first">Werner</forename><surname>Poewe</surname></persName><roleName type="degree">MD</roleName><affiliation>Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria</affiliation></author><author xml:id="author-8"><persName><forename type="first">Mark</forename><surname>Stacy</surname></persName><roleName type="degree">MD</roleName><affiliation>Department of Neurology, School of Medicine, Duke University Medical Center, North Carolina, Durham, USA</affiliation></author><author xml:id="author-9"><persName><forename type="first">Eduardo</forename><surname>Tolosa</surname></persName><roleName type="degree">MD</roleName><affiliation>Neurology Service, Hospital Clinic, Barcelona, Spain; Centro de Investigación Biomédica en Red Enfermedades Neurodegenerativas (CIBERNED), Barcelona, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain</affiliation></author><author xml:id="author-10"><persName><forename type="first">Haitao</forename><surname>Gao</surname></persName><roleName type="degree">PhD</roleName><affiliation>Novartis Pharmaceuticals Corporation, New Jersey, East Hanover, USA</affiliation></author><author xml:id="author-11"><persName><forename type="first">Jennifer</forename><surname>Nagel</surname></persName><roleName type="degree">PhD</roleName><affiliation>Novartis Pharma AG, Basel, Switzerland</affiliation></author><author xml:id="author-12"><persName><forename type="first">Martin</forename><surname>Merschhemke</surname></persName><roleName type="degree">MD</roleName><affiliation>Novartis Pharma AG, Basel, Switzerland</affiliation></author><author xml:id="author-13"><persName><forename type="first">Ana</forename><surname>Graf</surname></persName><roleName type="degree">MD</roleName><affiliation>Novartis Pharma AG, Basel, Switzerland</affiliation></author><author xml:id="author-14"><persName><forename type="first">Christopher</forename><surname>Kenney</surname></persName><roleName type="degree">MD</roleName><affiliation>Novartis Pharmaceuticals Corporation, New Jersey, East Hanover, USA</affiliation></author><author xml:id="author-15"><persName><forename type="first">Claudia</forename><surname>Trenkwalder</surname></persName><roleName type="degree">MD</roleName><affiliation>Paracelsus‐Elena‐Klinik, Kassel, Department of Neurosurgery, University Medical Center of Goettingen, Goettingen, 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>Blackwell Publishing Ltd</publisher><date type="published" when="2013-11"></date><biblScope unit="volume">28</biblScope><biblScope unit="issue">13</biblScope><biblScope unit="page" from="1838">1838</biblScope><biblScope unit="page" to="1846">1846</biblScope></imprint></monogr><idno type="istex">9A0BBD00C61270CF3E504E6B62F0E37B9F2B3155</idno><idno type="DOI">10.1002/mds.25561</idno><idno type="ArticleID">MDS25561</idno></biblStruct></sourceDesc></fileDesc><profileDesc><creation><date>2013-05-27</date></creation><langUsage><language ident="en">en</language></langUsage><abstract><p>AFQ056 is a novel, selective metabotropic glutamate receptor 5 antagonist. This was a 13‐week, double‐blind, placebo‐controlled study. Patients with Parkinson's disease and moderate‐to‐severe levodopa (l‐dopa)‐induced dyskinesia who were receiving stable l‐dopa/anti‐parkinsonian treatment and were not currently receiving amantadine were randomized to receive either AFQ056 (at doses of 20, 50, 100, 150, or 200 mg daily) or placebo (1:1:1:1:2:3 ratio) for 12 weeks. The primary outcome was the modified Abnormal Involuntary Movements Scale. Secondary outcomes included the 26‐item Parkinson's Disease Dyskinesia Scale, the Patient's/Clinician's Global Impression of Change, and the Unified Parkinson's Disease Rating Scale parts III (motor evaluation) and IV (severity of motor complications). Safety was assessed. In total, 98 of 133 (73.7%) AFQ056‐treated patients and 47 of 64 (73.4%) patients in the placebo group completed the study. Baseline characteristics were comparable. Patients randomized to AFQ056 200 mg daily administered in 2 doses demonstrated significant improvements at Week 12 on the modified Abnormal Involuntary Movements Scale compared with placebo (difference, −2.8; 95% confidence interval [CI], −5.2, −0.4; P = 0.007). Based on final actual doses, there was a dose‐response relationship on the modified Abnormal Involuntary Movements Scale, with 200 mg daily demonstrating the most robust effect (difference, −3.6; 95% CI, −7.0, −0.3; P = 0.012). Improvements in dyskinesia were supported by change on Unified Parkinson's Disease Rating Scale part IV item 32 (50 mg daily: difference, −0.7; 95% CI, −1.1, −0.2; P = 0.003; 200 mg daily: difference, −0.5; 95% CI, −0.8, −0.1; P = 0.005). No significant changes were observed on the 26‐item Parkinson's Disease Dyskinesia Scale, the Unified Parkinson's Disease Rating Scale part IV item 33 or items 32 and 33, or the Patient's/Clinician's Global Impression of Change. Unified Parkinson's Disease Rating Scale part III scores were not significantly changed, indicating no worsening of motor symptoms. The most common adverse events (with incidence greater with AFQ056 than with placebo) were dizziness, hallucination, fatigue, nasopharyngitis, diarrhea, and insomnia. AFQ056 demonstrated anti‐dyskinetic efficacy in this population without worsening underlying motor symptoms. These results will guide dose selection for future clinical trials. © 2013 International Parkinson and Movement Disorder Society</p></abstract><textClass><keywords scheme="keyword"><list><head>keywords</head><item><term>Parkinson's disease</term></item><item><term>levodopa (l‐dopa)</term></item><item><term>glutamate antagonists</term></item><item><term>AFQ056</term></item><item><term>dyskinesias</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="2012-11-02">Received</change><change when="2013-05-09">Registration</change><change when="2013-05-27">Created</change><change when="2013-11">Published</change></revisionDesc></teiHeader></istex:fulltextTEI><json:item><extension>txt</extension><original>false</original><mimetype>text/plain</mimetype><uri>https://api-v5.istex.fr/document/9A0BBD00C61270CF3E504E6B62F0E37B9F2B3155/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" xml:id="mds25561"><header><publicationMeta level="product"><doi origin="wiley" 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" sort="MOVEMENT DISORDERS">Movement Disorders</title><title type="short">Mov Disord.</title></titleGroup></publicationMeta><publicationMeta level="part" position="130"><doi>10.1002/mds.v28.13</doi><copyright ownership="thirdParty">© 2013 Movement Disorder Society</copyright><numberingGroup><numbering type="journalVolume" number="28">28</numbering><numbering type="journalIssue">13</numbering></numberingGroup><coverDate startDate="2013-11">November 2013</coverDate></publicationMeta><publicationMeta level="unit" position="190" type="article" status="forIssue"><doi>10.1002/mds.25561</doi><idGroup><id type="unit" value="MDS25561"></id></idGroup><countGroup><count type="pageTotal" number="9"></count></countGroup><titleGroup><title type="articleCategory">Research Article</title><title type="tocHeading1">Research Articles</title></titleGroup><copyright ownership="thirdParty">© 2013 Movement Disorder Society</copyright><eventGroup><event type="manuscriptReceived" date="2012-11-02"></event><event type="manuscriptRevised" date="2013-05-02"></event><event type="manuscriptAccepted" date="2013-05-09"></event><event type="xmlCreated" agent="Cenveo Publisher Services" date="2013-05-27"></event><event type="xmlConverted" agent="Converter:WILEY_ML3G_TO_WILEY_ML3GV2 version:3.2.6 mode:FullText" date="2013-11-13"></event><event type="publishedOnlineEarlyUnpaginated" date="2013-07-12"></event><event type="firstOnline" date="2013-07-12"></event><event type="publishedOnlineFinalForm" date="2013-11-13"></event><event type="xmlConverted" agent="Converter:WML3G_To_WML3G version:4.6.4 mode:FullText" date="2015-10-03"></event></eventGroup><numberingGroup><numbering type="pageFirst">1838</numbering><numbering type="pageLast">1846</numbering></numberingGroup><correspondenceTo><b>Correspondence to:</b> Dr. Fabrizio Stocchi, Department of Neuroscience, IRCCS San Raffaele, Via Della Pisana, 235, 00163 Rome, Italy; <email>fabrizio.stocchi@fastwebnet.it</email></correspondenceTo><linkGroup><link type="toTypesetVersion" href="file:MDS.MDS25561.pdf"></link></linkGroup></publicationMeta><contentMeta><titleGroup><title type="main">AFQ056 in Parkinson patients with levodopa‐induced dyskinesia: 13‐week, randomized, dose‐finding study</title><title type="short">AFQ056 treatment of <sc>l</sc>‐Dopa–Induced Dyskinesia</title><title type="shortAuthors">Stocchi et al.</title></titleGroup><creators><creator affiliationRef="#mds25561-aff-0001" corresponding="yes" creatorRole="author" xml:id="mds25561-cr-0001"><personName><givenNames>Fabrizio</givenNames><familyName>Stocchi</familyName><degrees>MD</degrees></personName></creator><creator affiliationRef="#mds25561-aff-0002" creatorRole="author" xml:id="mds25561-cr-0002"><personName><givenNames>Olivier</givenNames><familyName>Rascol</familyName><degrees>MD, PhD</degrees></personName></creator><creator affiliationRef="#mds25561-aff-0003" creatorRole="author" xml:id="mds25561-cr-0003"><personName><givenNames>Alain</givenNames><familyName>Destee</familyName><degrees>MD</degrees></personName></creator><creator affiliationRef="#mds25561-aff-0004" creatorRole="author" xml:id="mds25561-cr-0004"><personName><givenNames>Nobutaka</givenNames><familyName>Hattori</familyName><degrees>MD</degrees></personName></creator><creator affiliationRef="#mds25561-aff-0005" creatorRole="author" xml:id="mds25561-cr-0005"><personName><givenNames>Robert A.</givenNames><familyName>Hauser</familyName><degrees>MD</degrees></personName></creator><creator affiliationRef="#mds25561-aff-0006" creatorRole="author" xml:id="mds25561-cr-0006"><personName><givenNames>Anthony E.</givenNames><familyName>Lang</familyName><degrees>MD</degrees></personName></creator><creator affiliationRef="#mds25561-aff-0007" creatorRole="author" xml:id="mds25561-cr-0007"><personName><givenNames>Werner</givenNames><familyName>Poewe</familyName><degrees>MD</degrees></personName></creator><creator affiliationRef="#mds25561-aff-0008" creatorRole="author" xml:id="mds25561-cr-0008"><personName><givenNames>Mark</givenNames><familyName>Stacy</familyName><degrees>MD</degrees></personName></creator><creator affiliationRef="#mds25561-aff-0009" creatorRole="author" xml:id="mds25561-cr-0009"><personName><givenNames>Eduardo</givenNames><familyName>Tolosa</familyName><degrees>MD</degrees></personName></creator><creator affiliationRef="#mds25561-aff-0010" creatorRole="author" xml:id="mds25561-cr-0010"><personName><givenNames>Haitao</givenNames><familyName>Gao</familyName><degrees>PhD</degrees></personName></creator><creator affiliationRef="#mds25561-aff-0011" creatorRole="author" xml:id="mds25561-cr-0011"><personName><givenNames>Jennifer</givenNames><familyName>Nagel</familyName><degrees>PhD</degrees></personName></creator><creator affiliationRef="#mds25561-aff-0011" creatorRole="author" xml:id="mds25561-cr-0012"><personName><givenNames>Martin</givenNames><familyName>Merschhemke</familyName><degrees>MD</degrees></personName></creator><creator affiliationRef="#mds25561-aff-0011" creatorRole="author" xml:id="mds25561-cr-0013"><personName><givenNames>Ana</givenNames><familyName>Graf</familyName><degrees>MD</degrees></personName></creator><creator affiliationRef="#mds25561-aff-0010" creatorRole="author" xml:id="mds25561-cr-0014"><personName><givenNames>Christopher</givenNames><familyName>Kenney</familyName><degrees>MD</degrees></personName></creator><creator affiliationRef="#mds25561-aff-0012" creatorRole="author" xml:id="mds25561-cr-0015"><personName><givenNames>Claudia</givenNames><familyName>Trenkwalder</familyName><degrees>MD</degrees></personName></creator></creators><affiliationGroup><affiliation countryCode="IT" type="organization" xml:id="mds25561-aff-0001"><orgName>Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele Pisana</orgName><address><city>Rome</city><country>Italy</country></address></affiliation><affiliation countryCode="FR" type="organization" xml:id="mds25561-aff-0002"><orgDiv>Institut National de la Santé et de la Recherche Médicale (INSERM) CIC9302‐UMR825 and Departments of Neurosciences and Clinical Pharmacology</orgDiv><orgName>Toulouse University Hospital and University of Toulouse III</orgName><address><city>Toulouse</city><country>France</country></address></affiliation><affiliation countryCode="FR" type="organization" xml:id="mds25561-aff-0003"><orgName>Lille North of France University, Lille University Hospital, Movement Disorders Unit</orgName><address><street>INSERM U837</street><city>Lille</city><country>France</country></address></affiliation><affiliation countryCode="JP" type="organization" xml:id="mds25561-aff-0004"><orgName>Department of Neurology, Juntendo University School of Medicine</orgName><address><city>Tokyo</city><country>Japan</country></address></affiliation><affiliation countryCode="US" type="organization" xml:id="mds25561-aff-0005"><orgDiv>Department of Neurology</orgDiv><orgName>University of South Florida</orgName><address><city>Tampa</city><countryPart>Florida</countryPart><country>USA</country></address></affiliation><affiliation countryCode="CA" type="organization" xml:id="mds25561-aff-0006"><orgDiv>Edmond J. Safra Program in Parkinson's Disease</orgDiv><orgName>Toronto Western Hospital, University of Toronto</orgName><address><city>Toronto</city><countryPart>Ontario</countryPart><country>Canada</country></address></affiliation><affiliation countryCode="AT" type="organization" xml:id="mds25561-aff-0007"><orgDiv>Department of Neurology</orgDiv><orgName>Medical University of Innsbruck</orgName><address><city>Innsbruck</city><country>Austria</country></address></affiliation><affiliation countryCode="US" type="organization" xml:id="mds25561-aff-0008"><orgDiv>Department of Neurology</orgDiv><orgName>School of Medicine</orgName><orgName>Duke University Medical Center</orgName><address><city>Durham</city><countryPart>North Carolina</countryPart><country>USA</country></address></affiliation><affiliation countryCode="ES" type="organization" xml:id="mds25561-aff-0009"><orgName>Neurology Service, Hospital Clinic, Barcelona, Spain; Centro de Investigación Biomédica en Red Enfermedades Neurodegenerativas (CIBERNED), Barcelona, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)</orgName><address><countryPart>Barcelona</countryPart><country>Spain</country></address></affiliation><affiliation countryCode="US" type="organization" xml:id="mds25561-aff-0010"><orgName>Novartis Pharmaceuticals Corporation</orgName><address><city>East Hanover</city><countryPart>New Jersey</countryPart><country>USA</country></address></affiliation><affiliation countryCode="CH" type="organization" xml:id="mds25561-aff-0011"><orgName>Novartis Pharma AG</orgName><address><city>Basel</city><country>Switzerland</country></address></affiliation><affiliation countryCode="DE" type="organization" xml:id="mds25561-aff-0012"><orgDiv>Paracelsus‐Elena‐Klinik</orgDiv><orgDiv>Kassel</orgDiv><orgDiv>Department of Neurosurgery</orgDiv><orgName>University Medical Center of Goettingen</orgName><address><city>Goettingen</city><country>Germany</country></address></affiliation></affiliationGroup><keywordGroup type="author"><keyword xml:id="mds25561-kwd-0001">Parkinson's disease</keyword><keyword xml:id="mds25561-kwd-0002">levodopa (<sc>l</sc>‐dopa)</keyword><keyword xml:id="mds25561-kwd-0003">glutamate antagonists</keyword><keyword xml:id="mds25561-kwd-0004">AFQ056</keyword><keyword xml:id="mds25561-kwd-0005">dyskinesias</keyword></keywordGroup><fundingInfo><fundingAgency>Novartis Pharma AG (Basel, Switzerland)</fundingAgency><fundingNumber>NCT00986414</fundingNumber></fundingInfo><supportingInformation><p>Additional Supporting Information may be found in the online version of this article.</p><supportingInfoItem><mediaResource alt="application" href="urn-x:wiley:08853185:media:mds25561:mds25561-sup-0001-suppfig1"></mediaResource><caption><b>SUPPORTING FIG. 1</b>. The study design is illustrated. Enrolled patients were randomized to receive 20 mg/day, 50 mg/day, 100 mg/day, 150 mg/day, or 200 mg/day AFQ056 or placebo (1:1:1:1:2:3 ratio) in a 12‐week, double‐blind treatment phase. Patients were titrated at 1‐week intervals to their target or highest tolerated dose. With the exception of the 20 mg/day AFQ056 group, all active‐treated patients were initiated on 50 mg/day AFQ056. At the beginning of week 13, active‐treated patients were randomized to a 1‐week taper‐off regimen with AFQ056 or placebo. The 20 mg/day AFQ056 group received 20 mg/day AFQ056 or placebo for 1 week, and the 50 mg/day AFQ056 group received 50 mg/day AFQ056 or placebo for 1 week. The 100 mg/day, 150 mg/day, and 200 mg/day AFQ056 groups received either 100 mg/day AFQ056 for 3 days followed by 50 mg/day AFQ056 for 4 days (1 week total duration) or placebo for 1 week.</caption></supportingInfoItem><supportingInfoItem><mediaResource alt="application" href="urn-x:wiley:08853185:media:mds25561:mds25561-sup-0002-supptab1"></mediaResource><caption><b>Supporting Table 1</b>. Summary of the final actual dose of AFQ056 received at the end of the treatment phase, by randomized dose</caption></supportingInfoItem><supportingInfoItem><mediaResource alt="application" href="urn-x:wiley:08853185:media:mds25561:mds25561-sup-0003-suppinfo"></mediaResource><caption>Supporting Information.</caption></supportingInfoItem></supportingInformation><abstractGroup><abstract type="main"><title type="main">ABSTRACT</title><p>AFQ056 is a novel, selective metabotropic glutamate receptor 5 antagonist. This was a 13‐week, double‐blind, placebo‐controlled study. Patients with Parkinson's disease and moderate‐to‐severe levodopa (<sc>l</sc>‐dopa)‐induced dyskinesia who were receiving stable <sc>l</sc>‐dopa/anti‐parkinsonian treatment and were not currently receiving amantadine were randomized to receive either AFQ056 (at doses of 20, 50, 100, 150, or 200 mg daily) or placebo (1:1:1:1:2:3 ratio) for 12 weeks. The primary outcome was the modified Abnormal Involuntary Movements Scale. Secondary outcomes included the 26‐item Parkinson's Disease Dyskinesia Scale, the Patient's/Clinician's Global Impression of Change, and the Unified Parkinson's Disease Rating Scale parts III (motor evaluation) and IV (severity of motor complications). Safety was assessed. In total, 98 of 133 (73.7%) AFQ056‐treated patients and 47 of 64 (73.4%) patients in the placebo group completed the study. Baseline characteristics were comparable. Patients randomized to AFQ056 200 mg daily administered in 2 doses demonstrated significant improvements at Week 12 on the modified Abnormal Involuntary Movements Scale compared with placebo (difference, −2.8; 95% confidence interval [CI], −5.2, −0.4; <i>P</i> = 0.007). Based on final actual doses, there was a dose‐response relationship on the modified Abnormal Involuntary Movements Scale, with 200 mg daily demonstrating the most robust effect (difference, −3.6; 95% CI, −7.0, −0.3; <i>P</i> = 0.012). Improvements in dyskinesia were supported by change on Unified Parkinson's Disease Rating Scale part IV item 32 (50 mg daily: difference, −0.7; 95% CI, −1.1, −0.2; <i>P</i> = 0.003; 200 mg daily: difference, −0.5; 95% CI, −0.8, −0.1; <i>P</i> = 0.005). No significant changes were observed on the 26‐item Parkinson's Disease Dyskinesia Scale, the Unified Parkinson's Disease Rating Scale part IV item 33 or items 32 and 33, or the Patient's/Clinician's Global Impression of Change. Unified Parkinson's Disease Rating Scale part III scores were not significantly changed, indicating no worsening of motor symptoms. The most common adverse events (with incidence greater with AFQ056 than with placebo) were dizziness, hallucination, fatigue, nasopharyngitis, diarrhea, and insomnia. AFQ056 demonstrated anti‐dyskinetic efficacy in this population without worsening underlying motor symptoms. These results will guide dose selection for future clinical trials. © 2013 International Parkinson and Movement Disorder Society</p></abstract></abstractGroup></contentMeta><noteGroup><note xml:id="mds25561-note-0001"><p><b>Funding agencies:</b> This study was funded by Novartis Pharma AG (Basel, Switzerland)</p></note><note xml:id="mds25561-note-0002"><p>This study is registered (NCT00986414).</p></note><note xml:id="mds25561-note-0003"><p><b>Relevant conflicts of interest/financial disclosures:</b> Haitao Gao and Christopher Kenney are employees of Novartis Pharmaceuticals Corporation. Jennifer Nagel, Martin Merschhemke, and Ana Graf are employees of Novartis Pharma AG. Fabrizio Stocchi, Olivier Rascol, Alain Destee, Robert A. Hauser, Mark Stacy, and Claudia Trenkwalder have served on AFQ056 advisory board(s). Alain Destee received honoraria for consultancy from Novartis in the context of Clinical Drug development programs for Parkinson's disease. Werner Poewe has received honoraria for consultancy and lecture fees from Novartis AG in the context of clinical drug development programs for Parkinson's disease.</p></note><note xml:id="mds25561-note-0004"><p><b>Mark Stacy</b> Received Grant/Research Support from Ceregene, Michael J. Fox Foundation, NIH, Parkinson Study Group and has served as a consultant for Consultant Allergan, Biotie, Chelsea, General Electric, Johnson & Johnson, Lilly, Merz, Neuronova, Novartis, Osmotica, SK Life Sciences, UCB.</p></note><note xml:id="mds25561-note-0005"><p>Full financial disclosures and author roles may be found in the online version of this article.</p></note></noteGroup></header></component></istex:document></istex:metadataXml><mods version="3.6"><titleInfo lang="en"><title>AFQ056 in Parkinson patients with levodopa‐induced dyskinesia: 13‐week, randomized, dose‐finding study</title></titleInfo><titleInfo type="abbreviated" lang="en"><title>AFQ056 treatment of l‐Dopa–Induced Dyskinesia</title></titleInfo><titleInfo type="alternative" contentType="CDATA" lang="en"><title>AFQ056 in Parkinson patients with levodopa‐induced dyskinesia: 13‐week, randomized, dose‐finding study</title></titleInfo><name type="personal"><namePart type="given">Fabrizio</namePart><namePart type="family">Stocchi</namePart><namePart type="termsOfAddress">MD</namePart><affiliation>Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele Pisana, Rome, Italy</affiliation><affiliation>E-mail: fabrizio.stocchi@fastwebnet.it</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>Institut National de la Santé et de la Recherche Médicale (INSERM) CIC9302‐UMR825 and Departments of Neurosciences and Clinical Pharmacology, Toulouse University Hospital and University of Toulouse III, Toulouse, France</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Alain</namePart><namePart type="family">Destee</namePart><namePart type="termsOfAddress">MD</namePart><affiliation>Lille North of France University, Lille University Hospital, Movement Disorders Unit, INSERM U837, Lille, France</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Nobutaka</namePart><namePart type="family">Hattori</namePart><namePart type="termsOfAddress">MD</namePart><affiliation>Department of Neurology, Juntendo University School of Medicine, Tokyo, Japan</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Robert A.</namePart><namePart type="family">Hauser</namePart><namePart type="termsOfAddress">MD</namePart><affiliation>Department of Neurology, University of South Florida, Florida, Tampa, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Anthony E.</namePart><namePart type="family">Lang</namePart><namePart type="termsOfAddress">MD</namePart><affiliation>Edmond J. Safra Program in Parkinson's Disease, Toronto Western Hospital, University of Toronto, Ontario, Toronto, Canada</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 of Innsbruck, Innsbruck, Austria</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Mark</namePart><namePart type="family">Stacy</namePart><namePart type="termsOfAddress">MD</namePart><affiliation>Department of Neurology, School of Medicine, Duke University Medical Center, North Carolina, Durham, USA</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, Barcelona, Spain; Centro de Investigación Biomédica en Red Enfermedades Neurodegenerativas (CIBERNED), Barcelona, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Haitao</namePart><namePart type="family">Gao</namePart><namePart type="termsOfAddress">PhD</namePart><affiliation>Novartis Pharmaceuticals Corporation, New Jersey, East Hanover, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Jennifer</namePart><namePart type="family">Nagel</namePart><namePart type="termsOfAddress">PhD</namePart><affiliation>Novartis Pharma AG, Basel, Switzerland</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Martin</namePart><namePart type="family">Merschhemke</namePart><namePart type="termsOfAddress">MD</namePart><affiliation>Novartis Pharma AG, Basel, Switzerland</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Ana</namePart><namePart type="family">Graf</namePart><namePart type="termsOfAddress">MD</namePart><affiliation>Novartis Pharma AG, Basel, Switzerland</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Christopher</namePart><namePart type="family">Kenney</namePart><namePart type="termsOfAddress">MD</namePart><affiliation>Novartis Pharmaceuticals Corporation, New Jersey, East Hanover, USA</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, Department of Neurosurgery, University Medical Center of Goettingen, Goettingen, Germany</affiliation><role><roleTerm type="text">author</roleTerm></role></name><typeOfResource>text</typeOfResource><genre type="article" displayLabel="article"></genre><originInfo><publisher>Blackwell Publishing Ltd</publisher><dateIssued encoding="w3cdtf">2013-11</dateIssued><dateCreated encoding="w3cdtf">2013-05-27</dateCreated><dateCaptured encoding="w3cdtf">2012-11-02</dateCaptured><dateValid encoding="w3cdtf">2013-05-09</dateValid><copyrightDate encoding="w3cdtf">2013</copyrightDate></originInfo><language><languageTerm type="code" authority="rfc3066">en</languageTerm><languageTerm type="code" authority="iso639-2b">eng</languageTerm></language><physicalDescription><internetMediaType>text/html</internetMediaType></physicalDescription><abstract>AFQ056 is a novel, selective metabotropic glutamate receptor 5 antagonist. This was a 13‐week, double‐blind, placebo‐controlled study. Patients with Parkinson's disease and moderate‐to‐severe levodopa (l‐dopa)‐induced dyskinesia who were receiving stable l‐dopa/anti‐parkinsonian treatment and were not currently receiving amantadine were randomized to receive either AFQ056 (at doses of 20, 50, 100, 150, or 200 mg daily) or placebo (1:1:1:1:2:3 ratio) for 12 weeks. The primary outcome was the modified Abnormal Involuntary Movements Scale. Secondary outcomes included the 26‐item Parkinson's Disease Dyskinesia Scale, the Patient's/Clinician's Global Impression of Change, and the Unified Parkinson's Disease Rating Scale parts III (motor evaluation) and IV (severity of motor complications). Safety was assessed. In total, 98 of 133 (73.7%) AFQ056‐treated patients and 47 of 64 (73.4%) patients in the placebo group completed the study. Baseline characteristics were comparable. Patients randomized to AFQ056 200 mg daily administered in 2 doses demonstrated significant improvements at Week 12 on the modified Abnormal Involuntary Movements Scale compared with placebo (difference, −2.8; 95% confidence interval [CI], −5.2, −0.4; P = 0.007). Based on final actual doses, there was a dose‐response relationship on the modified Abnormal Involuntary Movements Scale, with 200 mg daily demonstrating the most robust effect (difference, −3.6; 95% CI, −7.0, −0.3; P = 0.012). Improvements in dyskinesia were supported by change on Unified Parkinson's Disease Rating Scale part IV item 32 (50 mg daily: difference, −0.7; 95% CI, −1.1, −0.2; P = 0.003; 200 mg daily: difference, −0.5; 95% CI, −0.8, −0.1; P = 0.005). No significant changes were observed on the 26‐item Parkinson's Disease Dyskinesia Scale, the Unified Parkinson's Disease Rating Scale part IV item 33 or items 32 and 33, or the Patient's/Clinician's Global Impression of Change. Unified Parkinson's Disease Rating Scale part III scores were not significantly changed, indicating no worsening of motor symptoms. The most common adverse events (with incidence greater with AFQ056 than with placebo) were dizziness, hallucination, fatigue, nasopharyngitis, diarrhea, and insomnia. AFQ056 demonstrated anti‐dyskinetic efficacy in this population without worsening underlying motor symptoms. These results will guide dose selection for future clinical trials. © 2013 International Parkinson and Movement Disorder Society</abstract><note type="funding">Novartis Pharma AG (Basel, Switzerland) - No. NCT00986414; </note><subject><genre>keywords</genre><topic>Parkinson's disease</topic><topic>levodopa (l‐dopa)</topic><topic>glutamate antagonists</topic><topic>AFQ056</topic><topic>dyskinesias</topic></subject><relatedItem type="host"><titleInfo><title>Movement Disorders</title></titleInfo><titleInfo type="abbreviated"><title>Mov Disord.</title></titleInfo><genre type="journal">journal</genre><note type="content"> Additional Supporting Information may be found in the online version of this article.Supporting Info Item: SUPPORTING FIG. 1. The study design is illustrated. Enrolled patients were randomized to receive 20 mg/day, 50 mg/day, 100 mg/day, 150 mg/day, or 200 mg/day AFQ056 or placebo (1:1:1:1:2:3 ratio) in a 12‐week, double‐blind treatment phase. Patients were titrated at 1‐week intervals to their target or highest tolerated dose. With the exception of the 20 mg/day AFQ056 group, all active‐treated patients were initiated on 50 mg/day AFQ056. At the beginning of week 13, active‐treated patients were randomized to a 1‐week taper‐off regimen with AFQ056 or placebo. The 20 mg/day AFQ056 group received 20 mg/day AFQ056 or placebo for 1 week, and the 50 mg/day AFQ056 group received 50 mg/day AFQ056 or placebo for 1 week. The 100 mg/day, 150 mg/day, and 200 mg/day AFQ056 groups received either 100 mg/day AFQ056 for 3 days followed by 50 mg/day AFQ056 for 4 days (1 week total duration) or placebo for 1 week. - Supporting Table 1. Summary of the final actual dose of AFQ056 received at the end of the treatment phase, by randomized dose - Supporting Information. - </note><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>2013</date><detail type="volume"><caption>vol.</caption><number>28</number></detail><detail type="issue"><caption>no.</caption><number>13</number></detail><extent unit="pages"><start>1838</start><end>1846</end><total>9</total></extent></part></relatedItem><identifier type="istex">9A0BBD00C61270CF3E504E6B62F0E37B9F2B3155</identifier><identifier type="DOI">10.1002/mds.25561</identifier><identifier type="ArticleID">MDS25561</identifier><accessCondition type="use and reproduction" contentType="copyright">© 2013 Movement Disorder Society© 2013 Movement Disorder Society</accessCondition><recordInfo><recordContentSource>WILEY</recordContentSource></recordInfo></mods></metadata><serie></serie></istex></record>Pour manipuler ce document sous Unix (Dilib)
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