A Phase 2A Trial of the Novel mGluR5-Negative Allosteric Modulator Dipraglurant for Levodopa-Induced Dyskinesia in Parkinson's Disease.
Identifieur interne : 000079 ( Main/Exploration ); précédent : 000078; suivant : 000080A Phase 2A Trial of the Novel mGluR5-Negative Allosteric Modulator Dipraglurant for Levodopa-Induced Dyskinesia in Parkinson's Disease.
Auteurs : François Tison [France] ; Charlotte Keywood [Suisse] ; Mark Wakefield [France] ; Franck Durif [France] ; Jean-Christophe Corvol [France] ; Karla Eggert [France] ; Mark Lew [États-Unis] ; Stuart Isaacson [États-Unis] ; Erwan Bezard [France] ; Sonia-Maria Poli [Suisse] ; Christopher G. Goetz [États-Unis] ; Claudia Trenkwalder [Allemagne] ; Olivier Rascol [France]Source :
- Movement Disorders [ 0885-3185 ] ; 2016-05-23.
Abstract
The metabotropic glutamate receptor 5-negative allosteric modulator dipraglurant reduces levodopa-induced dyskinesia in the MPTP-macaque model. The objective of this study was to assess the safety, tolerability (primary objective), and efficacy (secondary objective) of dipraglurant on levodopa-induced dyskinesia in Parkinson's disease (PD). The study was a phase 2A double-blind, placebo-controlled, randomized (2:1), 4-week, parallel-group, multicenter dose-escalation (from 50 mg once daily to 100 mg 3 times daily) clinical trial involving 76 PD subjects with moderate to severe levodopa-induced dyskinesia. Safety and tolerability were assessed based on clinical and biological examination and adverse events recording. Secondary efficacy outcome measures included the modified Abnormal Involuntary Movement Scale, UPDRS, and diaries. Pharmacokinetics were measured at 3 visits following a single dose. Fifty-two patients were exposed to dipraglurant and 24 to placebo. There were no major safety concerns. Two subjects did not complete the study because of adverse events. Most frequent adverse events included dyskinesia, dizziness, nausea, and fatigue. Dipraglurant significantly reduced peak dose dyskinesia (modified Abnormal Involuntary Movement Scale) on day 1 (50 mg, 20%; P = 0.04) and on day 14 (100 mg, 32%; P =0 .04) and across a 3-hour postdose period on day 14 (P = 0.04). There was no evidence of worsening of parkinsonism. Dipraglurant was rapidly absorbed (tmax = 1 hour). The 100-mg dose led to a mean Cmax of 1844 ng/mL on day 28. Dipraglurant proved to be safe and well tolerated in its first administration to PD patients. Its efficacy in reversing levodopa-induced dyskinesia warrants further investigations in a larger number of patients. © 2016 International Parkinson and Movement Disorder Society.
Url:
DOI: 10.1002/mds.26659.
Affiliations:
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sort="Lew, Mark" uniqKey="Lew M" first="Mark" last="Lew">Mark Lew</name><affiliation wicri:level="1"><hal:affiliation type="laboratory" xml:id="struct-101482" status="INCOMING"> <orgName>USC Neuromuscular Center, Department of Neurology</orgName> <desc> <address> <addrLine>Keck School of Medicine Good Samaritan Hospital Los Angeles, CA 90017</addrLine> <country key="US"></country> </address> </desc> <listRelation> <relation active="#struct-85559" type="direct"></relation> </listRelation><tutelles><tutelle active="#struct-85559" type="direct"><org type="institution" xml:id="struct-85559" status="VALID"> <orgName>University of Southern California [Los Angeles]</orgName> <orgName type="acronym">USC</orgName> <desc> <address> <addrLine>Los Angeles, CA, 90089-0484, USA</addrLine> <country key="US"></country> </address> <ref type="url">http://www.usc.edu/</ref> </desc></org></tutelle></tutelles></hal:affiliation><country>États-Unis</country></affiliation></author><author><name sortKey="Isaacson, Stuart" sort="Isaacson, Stuart" uniqKey="Isaacson S" first="Stuart" last="Isaacson">Stuart Isaacson</name><affiliation wicri:level="1"><hal:affiliation type="laboratory" xml:id="struct-459381" status="INCOMING"> <orgName>Parkinson's Disease and Movement Disorders Center of Boca Raton</orgName> <desc> <address> <addrLine>Florida, USA</addrLine> <country key="US"></country> </address> </desc> <listRelation> <relation active="#struct-416329" type="direct"></relation> </listRelation><tutelles><tutelle active="#struct-416329" type="direct"><org type="institution" xml:id="struct-416329" status="INCOMING"> <orgName>Université Atlantique de Floride à Boca Raton</orgName> <desc> <address> <country key="US"></country> </address> </desc></org></tutelle></tutelles></hal:affiliation><country>États-Unis</country></affiliation></author><author><name sortKey="Bezard, Erwan" sort="Bezard, Erwan" uniqKey="Bezard E" first="Erwan" last="Bezard">Erwan Bezard</name><affiliation wicri:level="1"><hal:affiliation type="laboratory" xml:id="struct-244085" status="VALID"> <orgName>Institut des Maladies Neurodégénératives [Bordeaux]</orgName> <orgName type="acronym">IMN</orgName> <desc> <address> <addrLine>Bât. 3b 1er étage 146 Rue Léo Saignat 33076 Bordeaux </addrLine> <country key="FR"></country> </address> <ref type="url">http://imn-bordeaux.org/</ref> </desc> <listRelation> <relation active="#struct-259761" type="direct"></relation> <relation name="UMR5293" active="#struct-441569" type="direct"></relation> </listRelation><tutelles><tutelle active="#struct-259761" type="direct"><org type="institution" xml:id="struct-259761" status="VALID"> <orgName>Université de Bordeaux</orgName> <orgName type="acronym">UB</orgName> <desc> <address> <addrLine>35, place Pey Berland - 33076 Bordeaux</addrLine> <country key="FR"></country> </address> <ref type="url">http://www.u-bordeaux.fr/</ref> </desc></org></tutelle><tutelle name="UMR5293" active="#struct-441569" type="direct"><org type="institution" xml:id="struct-441569" status="VALID"> <idno type="IdRef">02636817X</idno> <idno type="ISNI">0000000122597504</idno> <orgName>Centre National de la Recherche Scientifique</orgName> <orgName type="acronym">CNRS</orgName> <date type="start">1939-10-19</date> <desc> <address> <country key="FR"></country> </address> <ref type="url">http://www.cnrs.fr/</ref> </desc></org></tutelle></tutelles></hal:affiliation><country>France</country><placeName><settlement type="city">Bordeaux</settlement><region type="region" nuts="2">Nouvelle-Aquitaine</region><region type="old region" nuts="2">Aquitaine</region></placeName><orgName type="university">Université de Bordeaux</orgName></affiliation></author><author><name sortKey="Poli, Sonia Maria" sort="Poli, Sonia Maria" uniqKey="Poli S" first="Sonia-Maria" last="Poli">Sonia-Maria Poli</name><affiliation wicri:level="1"><hal:affiliation type="laboratory" xml:id="struct-13839" status="INCOMING"> <orgName>Addex Pharmaceuticals SA, ADME/PK</orgName> <desc> <address> <addrLine>CH-1228 Plan les Ouates GE</addrLine> <country key="CH"></country> </address> <ref type="url">http://www.addexpharma.com</ref> </desc> <listRelation> <relation active="#struct-305927" type="direct"></relation> </listRelation><tutelles><tutelle active="#struct-305927" type="direct"><org type="institution" xml:id="struct-305927" status="INCOMING"> <orgName>Addex Pharmaceuticals</orgName> <desc> <address> <country key="FR"></country> </address> </desc></org></tutelle></tutelles></hal:affiliation><country>Suisse</country></affiliation></author><author><name sortKey="Goetz, Christopher G" sort="Goetz, Christopher G" uniqKey="Goetz C" first="Christopher G" last="Goetz">Christopher G. Goetz</name><affiliation wicri:level="1"><hal:affiliation type="laboratory" xml:id="struct-439108" status="INCOMING"> <orgName>The Graduate College, Rush University, Department of Neurological Sciences, Chicago, Illinois</orgName> <desc> <address> <country key="US"></country> </address> </desc> <listRelation> <relation active="#struct-439107" type="direct"></relation> </listRelation><tutelles><tutelle active="#struct-439107" type="direct"><org type="institution" xml:id="struct-439107" status="INCOMING"> <orgName>Department of Neurological Sciences, The Graduate College, Rush University, Chicago, Illinois, USA</orgName> <desc> <address> <country key="US"></country> </address> </desc></org></tutelle></tutelles></hal:affiliation><country>États-Unis</country></affiliation></author><author><name sortKey="Trenkwalder, Claudia" sort="Trenkwalder, Claudia" uniqKey="Trenkwalder C" first="Claudia" last="Trenkwalder">Claudia Trenkwalder</name><affiliation wicri:level="1"><hal:affiliation type="laboratory" xml:id="struct-459383" status="INCOMING"> <orgName>Paracelsus Elena Klinik</orgName> <desc> <address> <addrLine>Centre for Parkinson's Disease & Movement DisordersKassel, Germany</addrLine> <country key="DE"></country> </address> </desc> <listRelation> <relation active="#struct-459382" type="direct"></relation> </listRelation><tutelles><tutelle active="#struct-459382" type="direct"><org type="institution" xml:id="struct-459382" status="INCOMING"> <orgName>Centre for Parkinson's Disease & Movement Disorders, </orgName> <desc> <address> <addrLine>Kassel, Germany</addrLine> <country key="DE"></country> </address> </desc></org></tutelle></tutelles></hal:affiliation><country>Allemagne</country></affiliation></author><author><name sortKey="Rascol, Olivier" sort="Rascol, Olivier" uniqKey="Rascol O" first="Olivier" last="Rascol">Olivier Rascol</name><affiliation wicri:level="1"><hal:affiliation type="laboratory" xml:id="struct-203181" status="INCOMING"> <orgName>Pharmacologie Clinique et Neurosciences</orgName> <desc> <address> <addrLine>Pavillon Riser - Place du Docteur Baylac - TSA 40031 - 31059 Toulouse Cedex 9</addrLine> <country key="FR"></country> </address> </desc> <listRelation> <relation name="CIC9302" active="#struct-303623" type="direct"></relation> <relation active="#struct-300075" type="direct"></relation> <relation active="#struct-300779" type="direct"></relation> </listRelation><tutelles><tutelle name="CIC9302" active="#struct-303623" type="direct"><org type="institution" xml:id="struct-303623" status="VALID"> <idno type="IdRef">026388278</idno> <orgName>Institut National de la Santé et de la Recherche Médicale</orgName> <orgName type="acronym">INSERM</orgName> <desc> <address> <addrLine>101, rue de Tolbiac, 75013 Paris </addrLine> <country key="FR"></country> </address> <ref type="url">http://www.inserm.fr</ref> </desc></org></tutelle><tutelle active="#struct-300075" type="direct"><org type="institution" xml:id="struct-300075" status="VALID"> <orgName>CHU Toulouse [Toulouse]</orgName> <desc> <address> <addrLine>330 Avenue de Grande Bretagne, TSA 40031, 31059 Toulouse Cedex 09</addrLine> <country key="FR"></country> </address> </desc></org></tutelle><tutelle active="#struct-300779" type="direct"><org type="institution" xml:id="struct-300779" status="VALID"> <orgName>Hôpital Purpan</orgName> <desc> <address> <addrLine>Toulouse</addrLine> <country key="FR"></country> </address> </desc></org></tutelle></tutelles></hal:affiliation><country>France</country></affiliation></author></analytic><idno type="DOI">10.1002/mds.26659.</idno><series><title level="j">Movement Disorders</title><idno type="ISSN">0885-3185</idno><imprint><date type="datePub">2016-05-23</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">The metabotropic glutamate receptor 5-negative allosteric modulator dipraglurant reduces levodopa-induced dyskinesia in the MPTP-macaque model. The objective of this study was to assess the safety, tolerability (primary objective), and efficacy (secondary objective) of dipraglurant on levodopa-induced dyskinesia in Parkinson's disease (PD). The study was a phase 2A double-blind, placebo-controlled, randomized (2:1), 4-week, parallel-group, multicenter dose-escalation (from 50 mg once daily to 100 mg 3 times daily) clinical trial involving 76 PD subjects with moderate to severe levodopa-induced dyskinesia. Safety and tolerability were assessed based on clinical and biological examination and adverse events recording. Secondary efficacy outcome measures included the modified Abnormal Involuntary Movement Scale, UPDRS, and diaries. Pharmacokinetics were measured at 3 visits following a single dose. Fifty-two patients were exposed to dipraglurant and 24 to placebo. There were no major safety concerns. Two subjects did not complete the study because of adverse events. Most frequent adverse events included dyskinesia, dizziness, nausea, and fatigue. Dipraglurant significantly reduced peak dose dyskinesia (modified Abnormal Involuntary Movement Scale) on day 1 (50 mg, 20%; P = 0.04) and on day 14 (100 mg, 32%; P =0 .04) and across a 3-hour postdose period on day 14 (P = 0.04). There was no evidence of worsening of parkinsonism. Dipraglurant was rapidly absorbed (tmax = 1 hour). The 100-mg dose led to a mean Cmax of 1844 ng/mL on day 28. Dipraglurant proved to be safe and well tolerated in its first administration to PD patients. Its efficacy in reversing levodopa-induced dyskinesia warrants further investigations in a larger number of patients. © 2016 International Parkinson and Movement Disorder Society. </div></front></TEI><affiliations><list><country><li>Allemagne</li><li>France</li><li>Suisse</li><li>États-Unis</li></country><region><li>Aquitaine</li><li>Nouvelle-Aquitaine</li></region><settlement><li>Bordeaux</li></settlement><orgName><li>Université de Bordeaux</li></orgName></list><tree><country name="France"><region name="Nouvelle-Aquitaine"><name sortKey="Tison, Francois" sort="Tison, Francois" uniqKey="Tison F" first="François" last="Tison">François Tison</name></region><name sortKey="Bezard, Erwan" sort="Bezard, Erwan" uniqKey="Bezard E" first="Erwan" last="Bezard">Erwan Bezard</name><name sortKey="Corvol, Jean Christophe" sort="Corvol, Jean Christophe" uniqKey="Corvol J" first="Jean-Christophe" last="Corvol">Jean-Christophe Corvol</name><name sortKey="Durif, Franck" sort="Durif, Franck" uniqKey="Durif F" first="Franck" last="Durif">Franck Durif</name><name sortKey="Eggert, Karla" sort="Eggert, Karla" uniqKey="Eggert K" first="Karla" last="Eggert">Karla Eggert</name><name sortKey="Rascol, Olivier" sort="Rascol, Olivier" uniqKey="Rascol O" first="Olivier" last="Rascol">Olivier Rascol</name><name sortKey="Wakefield, Mark" sort="Wakefield, Mark" uniqKey="Wakefield M" first="Mark" last="Wakefield">Mark Wakefield</name></country><country name="Suisse"><noRegion><name sortKey="Keywood, Charlotte" sort="Keywood, Charlotte" uniqKey="Keywood C" first="Charlotte" last="Keywood">Charlotte Keywood</name></noRegion><name sortKey="Poli, Sonia Maria" sort="Poli, Sonia Maria" uniqKey="Poli S" first="Sonia-Maria" last="Poli">Sonia-Maria Poli</name></country><country name="États-Unis"><noRegion><name sortKey="Lew, Mark" sort="Lew, Mark" uniqKey="Lew M" first="Mark" last="Lew">Mark Lew</name></noRegion><name sortKey="Goetz, Christopher G" sort="Goetz, Christopher G" uniqKey="Goetz C" first="Christopher G" last="Goetz">Christopher G. Goetz</name><name sortKey="Isaacson, Stuart" sort="Isaacson, Stuart" uniqKey="Isaacson S" first="Stuart" last="Isaacson">Stuart Isaacson</name></country><country name="Allemagne"><noRegion><name sortKey="Trenkwalder, Claudia" sort="Trenkwalder, Claudia" uniqKey="Trenkwalder C" first="Claudia" last="Trenkwalder">Claudia Trenkwalder</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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