Adenosine A2A Receptor Antagonist Istradefylline (KW-6002) Reduces "Off' Time in Parkinson's Disease : A Double-Blind, Randomized, Multicenter Clinical Trial (6002-US-005)
Identifieur interne : 000649 ( PascalFrancis/Curation ); précédent : 000648; suivant : 000650Adenosine A2A Receptor Antagonist Istradefylline (KW-6002) Reduces "Off' Time in Parkinson's Disease : A Double-Blind, Randomized, Multicenter Clinical Trial (6002-US-005)
Auteurs : Peter A. Lewitt [États-Unis] ; M. Guttman [Canada] ; James W. Tetrud [États-Unis] ; Paul J. Tuite [États-Unis] ; Akihisa Mori [Japon] ; Philip Chaikin [États-Unis] ; Neil M. Sussman [États-Unis]Source :
- Annals of neurology [ 0364-5134 ] ; 2008.
Descripteurs français
- Pascal (Inist)
English descriptors
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Abstract
Objective: Based on new understanding of nondopaminergic pathways involved in Parkinson's disease (PD) pathophysiology, a selective adenosine A2A receptor antagonist, istradefylline, shows promise for the treatment of PD. Methods: Istradefylline (40mg/day) was studied in levodopa-treated PD subjects experiencing prominent wearing-off motor fluctuations. At 23 North American sites, 196 subjects were randomized in a double-blind, 12-week outpatient clinical trial of istradefylline (114 completing the trial) or placebo (58 completing the trial). The primary efficacy measure was change from baseline to end point in the percentage of daily awake "off" time, recorded by subjects using a patient PD diary. Secondary end points evaluated "on" time (including "on time with dyskinesia"), the Unified Parkinson's Disease Rating Scale, and a Clinical Global Impression-Improvement of Illness score. Clinical laboratory, electrocardiograms, vital signs, and adverse event monitoring comprised the safety monitoring. Results: After randomization, approximately 88% of subjects completed the double-blind period. Compared with baseline, the decrease of daily awake "off' time for istradefylline was a mean (± standard deviation) of -10.8 ± 16.6% (95% confidence interval, -13.46 to -7.52) and for placebo, -4.0 ± 15.7% (95% confidence interval, -7.73-0.31; p = 0.007 using two-way analysis of variance). This effect corresponded to changes from baseline in total daily awake "off' time of -1.8 ± 2.8 hours for istradefylline and -0.6 ± 2.7 hours for placebo (p = 0.005). Treatment-emergent adverse effects with istradefylline were generally mild. Interpretation: Istradefylline was safe, well tolerated, and offered a clinically meaningful reduction in "off' time without increased troublesome dyskinesia.
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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en" level="a">Adenosine A<sub>2A</sub> Receptor Antagonist Istradefylline (KW-6002) Reduces "Off' Time in Parkinson's Disease : A Double-Blind, Randomized, Multicenter Clinical Trial (6002-US-005)</title><author><name sortKey="Lewitt, Peter A" sort="Lewitt, Peter A" uniqKey="Lewitt P" first="Peter A." last="Lewitt">Peter A. Lewitt</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Department of Neurology, Henry Ford Hospital</s1><s3>USA</s3><sZ>1 aut.</sZ></inist:fA14><country>États-Unis</country></affiliation><affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Department of Neurology, Wayne State University School of Medicine</s1><s2>Detroit, MI</s2><s3>USA</s3><sZ>1 aut.</sZ></inist:fA14><country>États-Unis</country></affiliation></author><author><name sortKey="Guttman, M" sort="Guttman, M" uniqKey="Guttman M" first="M." last="Guttman">M. Guttman</name><affiliation wicri:level="1"><inist:fA14 i1="03"><s1>Division of Neurology, Department of Medicine, University of Toronto</s1><s2>Toronto, Ontario</s2><s3>CAN</s3><sZ>2 aut.</sZ></inist:fA14><country>Canada</country></affiliation></author><author><name sortKey="Tetrud, James W" sort="Tetrud, James W" uniqKey="Tetrud J" first="James W." last="Tetrud">James W. Tetrud</name><affiliation wicri:level="1"><inist:fA14 i1="04"><s1>The Parkinson Institute</s1><s2>Sunnyvale, CA</s2><s3>USA</s3><sZ>3 aut.</sZ></inist:fA14><country>États-Unis</country></affiliation></author><author><name sortKey="Tuite, Paul J" sort="Tuite, Paul J" uniqKey="Tuite P" first="Paul J." last="Tuite">Paul J. Tuite</name><affiliation wicri:level="1"><inist:fA14 i1="05"><s1>Department of Neurology, University of Minnesota</s1><s2>Minneapolis, MN</s2><s3>USA</s3><sZ>4 aut.</sZ></inist:fA14><country>États-Unis</country></affiliation></author><author><name sortKey="Mori, Akihisa" sort="Mori, Akihisa" uniqKey="Mori A" first="Akihisa" last="Mori">Akihisa Mori</name><affiliation wicri:level="1"><inist:fA14 i1="06"><s1>Kyowa Hakko Kogyo Co., Ltd</s1><s2>Tokyo</s2><s3>JPN</s3><sZ>5 aut.</sZ></inist:fA14><country>Japon</country></affiliation></author><author><name sortKey="Chaikin, Philip" sort="Chaikin, Philip" uniqKey="Chaikin P" first="Philip" last="Chaikin">Philip Chaikin</name><affiliation wicri:level="1"><inist:fA14 i1="07"><s1>Kyowa Pharmaceutical, Inc</s1><s2>Princeton, NJ</s2><s3>USA</s3><sZ>6 aut.</sZ><sZ>7 aut.</sZ></inist:fA14><country>États-Unis</country></affiliation></author><author><name sortKey="Sussman, Neil M" sort="Sussman, Neil M" uniqKey="Sussman N" first="Neil M." last="Sussman">Neil M. Sussman</name><affiliation wicri:level="1"><inist:fA14 i1="07"><s1>Kyowa Pharmaceutical, Inc</s1><s2>Princeton, NJ</s2><s3>USA</s3><sZ>6 aut.</sZ><sZ>7 aut.</sZ></inist:fA14><country>États-Unis</country></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">INIST</idno><idno type="inist">08-0192208</idno><date when="2008">2008</date><idno type="stanalyst">PASCAL 08-0192208 INIST</idno><idno type="RBID">Pascal:08-0192208</idno><idno type="wicri:Area/PascalFrancis/Corpus">000661</idno><idno type="wicri:Area/PascalFrancis/Curation">000649</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a">Adenosine A<sub>2A</sub> Receptor Antagonist Istradefylline (KW-6002) Reduces "Off' Time in Parkinson's Disease : A Double-Blind, Randomized, Multicenter Clinical Trial (6002-US-005)</title><author><name sortKey="Lewitt, Peter A" sort="Lewitt, Peter A" uniqKey="Lewitt P" first="Peter A." last="Lewitt">Peter A. Lewitt</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Department of Neurology, Henry Ford Hospital</s1><s3>USA</s3><sZ>1 aut.</sZ></inist:fA14><country>États-Unis</country></affiliation><affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Department of Neurology, Wayne State University School of Medicine</s1><s2>Detroit, MI</s2><s3>USA</s3><sZ>1 aut.</sZ></inist:fA14><country>États-Unis</country></affiliation></author><author><name sortKey="Guttman, M" sort="Guttman, M" uniqKey="Guttman M" first="M." last="Guttman">M. Guttman</name><affiliation wicri:level="1"><inist:fA14 i1="03"><s1>Division of Neurology, Department of Medicine, University of Toronto</s1><s2>Toronto, Ontario</s2><s3>CAN</s3><sZ>2 aut.</sZ></inist:fA14><country>Canada</country></affiliation></author><author><name sortKey="Tetrud, James W" sort="Tetrud, James W" uniqKey="Tetrud J" first="James W." last="Tetrud">James W. Tetrud</name><affiliation wicri:level="1"><inist:fA14 i1="04"><s1>The Parkinson Institute</s1><s2>Sunnyvale, CA</s2><s3>USA</s3><sZ>3 aut.</sZ></inist:fA14><country>États-Unis</country></affiliation></author><author><name sortKey="Tuite, Paul J" sort="Tuite, Paul J" uniqKey="Tuite P" first="Paul J." last="Tuite">Paul J. Tuite</name><affiliation wicri:level="1"><inist:fA14 i1="05"><s1>Department of Neurology, University of Minnesota</s1><s2>Minneapolis, MN</s2><s3>USA</s3><sZ>4 aut.</sZ></inist:fA14><country>États-Unis</country></affiliation></author><author><name sortKey="Mori, Akihisa" sort="Mori, Akihisa" uniqKey="Mori A" first="Akihisa" last="Mori">Akihisa Mori</name><affiliation wicri:level="1"><inist:fA14 i1="06"><s1>Kyowa Hakko Kogyo Co., Ltd</s1><s2>Tokyo</s2><s3>JPN</s3><sZ>5 aut.</sZ></inist:fA14><country>Japon</country></affiliation></author><author><name sortKey="Chaikin, Philip" sort="Chaikin, Philip" uniqKey="Chaikin P" first="Philip" last="Chaikin">Philip Chaikin</name><affiliation wicri:level="1"><inist:fA14 i1="07"><s1>Kyowa Pharmaceutical, Inc</s1><s2>Princeton, NJ</s2><s3>USA</s3><sZ>6 aut.</sZ><sZ>7 aut.</sZ></inist:fA14><country>États-Unis</country></affiliation></author><author><name sortKey="Sussman, Neil M" sort="Sussman, Neil M" uniqKey="Sussman N" first="Neil M." last="Sussman">Neil M. Sussman</name><affiliation wicri:level="1"><inist:fA14 i1="07"><s1>Kyowa Pharmaceutical, Inc</s1><s2>Princeton, NJ</s2><s3>USA</s3><sZ>6 aut.</sZ><sZ>7 aut.</sZ></inist:fA14><country>États-Unis</country></affiliation></author></analytic><series><title level="j" type="main">Annals of neurology</title><title level="j" type="abbreviated">Ann. neurol.</title><idno type="ISSN">0364-5134</idno><imprint><date when="2008">2008</date></imprint></series></biblStruct></sourceDesc><seriesStmt><title level="j" type="main">Annals of neurology</title><title level="j" type="abbreviated">Ann. neurol.</title><idno type="ISSN">0364-5134</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>A2A adenosine receptor</term><term>Clinical trial</term><term>Istradefylline</term><term>Multicenter study</term><term>Nervous system diseases</term><term>Parkinson disease</term></keywords><keywords scheme="Pascal" xml:lang="fr"><term>Maladie de Parkinson</term><term>Pathologie du système nerveux</term><term>Récepteur adénosinique A2A</term><term>Istradéfylline</term><term>Etude multicentrique</term><term>Essai clinique</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Objective: Based on new understanding of nondopaminergic pathways involved in Parkinson's disease (PD) pathophysiology, a selective adenosine A<sub>2A</sub> receptor antagonist, istradefylline, shows promise for the treatment of PD. Methods: Istradefylline (40mg/day) was studied in levodopa-treated PD subjects experiencing prominent wearing-off motor fluctuations. At 23 North American sites, 196 subjects were randomized in a double-blind, 12-week outpatient clinical trial of istradefylline (114 completing the trial) or placebo (58 completing the trial). The primary efficacy measure was change from baseline to end point in the percentage of daily awake "off" time, recorded by subjects using a patient PD diary. Secondary end points evaluated "on" time (including "on time with dyskinesia"), the Unified Parkinson's Disease Rating Scale, and a Clinical Global Impression-Improvement of Illness score. Clinical laboratory, electrocardiograms, vital signs, and adverse event monitoring comprised the safety monitoring. Results: After randomization, approximately 88% of subjects completed the double-blind period. Compared with baseline, the decrease of daily awake "off' time for istradefylline was a mean (± standard deviation) of -10.8 ± 16.6% (95% confidence interval, -13.46 to -7.52) and for placebo, -4.0 ± 15.7% (95% confidence interval, -7.73-0.31; p = 0.007 using two-way analysis of variance). This effect corresponded to changes from baseline in total daily awake "off' time of -1.8 ± 2.8 hours for istradefylline and -0.6 ± 2.7 hours for placebo (p = 0.005). Treatment-emergent adverse effects with istradefylline were generally mild. Interpretation: Istradefylline was safe, well tolerated, and offered a clinically meaningful reduction in "off' time without increased troublesome dyskinesia.</div></front></TEI><inist><standard h6="B"><pA><fA01 i1="01" i2="1"><s0>0364-5134</s0></fA01><fA02 i1="01"><s0>ANNED3</s0></fA02><fA03 i2="1"><s0>Ann. neurol.</s0></fA03><fA05><s2>63</s2></fA05><fA06><s2>3</s2></fA06><fA08 i1="01" i2="1" l="ENG"><s1>Adenosine A<sub>2A</sub> Receptor Antagonist Istradefylline (KW-6002) Reduces "Off' Time in Parkinson's Disease : A Double-Blind, Randomized, Multicenter Clinical Trial (6002-US-005)</s1></fA08><fA11 i1="01" i2="1"><s1>LEWITT (Peter A.)</s1></fA11><fA11 i1="02" i2="1"><s1>GUTTMAN (M.)</s1></fA11><fA11 i1="03" i2="1"><s1>TETRUD (James W.)</s1></fA11><fA11 i1="04" i2="1"><s1>TUITE (Paul J.)</s1></fA11><fA11 i1="05" i2="1"><s1>MORI (Akihisa)</s1></fA11><fA11 i1="06" i2="1"><s1>CHAIKIN (Philip)</s1></fA11><fA11 i1="07" i2="1"><s1>SUSSMAN (Neil M.)</s1></fA11><fA14 i1="01"><s1>Department of Neurology, Henry Ford Hospital</s1><s3>USA</s3><sZ>1 aut.</sZ></fA14><fA14 i1="02"><s1>Department of Neurology, Wayne State University School of Medicine</s1><s2>Detroit, MI</s2><s3>USA</s3><sZ>1 aut.</sZ></fA14><fA14 i1="03"><s1>Division of Neurology, Department of Medicine, University of Toronto</s1><s2>Toronto, Ontario</s2><s3>CAN</s3><sZ>2 aut.</sZ></fA14><fA14 i1="04"><s1>The Parkinson Institute</s1><s2>Sunnyvale, CA</s2><s3>USA</s3><sZ>3 aut.</sZ></fA14><fA14 i1="05"><s1>Department of Neurology, University of Minnesota</s1><s2>Minneapolis, MN</s2><s3>USA</s3><sZ>4 aut.</sZ></fA14><fA14 i1="06"><s1>Kyowa Hakko Kogyo Co., Ltd</s1><s2>Tokyo</s2><s3>JPN</s3><sZ>5 aut.</sZ></fA14><fA14 i1="07"><s1>Kyowa Pharmaceutical, Inc</s1><s2>Princeton, NJ</s2><s3>USA</s3><sZ>6 aut.</sZ><sZ>7 aut.</sZ></fA14><fA17 i1="01" i2="1"><s1>6002-US-005 Study Group</s1><s3>INC</s3></fA17><fA20><s1>295-302</s1></fA20><fA21><s1>2008</s1></fA21><fA23 i1="01"><s0>ENG</s0></fA23><fA43 i1="01"><s1>INIST</s1><s2>16555</s2><s5>354000183339310060</s5></fA43><fA44><s0>0000</s0><s1>© 2008 INIST-CNRS. All rights reserved.</s1></fA44><fA45><s0>24 ref.</s0></fA45><fA47 i1="01" i2="1"><s0>08-0192208</s0></fA47><fA60><s1>P</s1></fA60><fA61><s0>A</s0></fA61><fA64 i1="01" i2="1"><s0>Annals of neurology</s0></fA64><fA66 i1="01"><s0>GBR</s0></fA66><fC01 i1="01" l="ENG"><s0>Objective: Based on new understanding of nondopaminergic pathways involved in Parkinson's disease (PD) pathophysiology, a selective adenosine A<sub>2A</sub> receptor antagonist, istradefylline, shows promise for the treatment of PD. Methods: Istradefylline (40mg/day) was studied in levodopa-treated PD subjects experiencing prominent wearing-off motor fluctuations. At 23 North American sites, 196 subjects were randomized in a double-blind, 12-week outpatient clinical trial of istradefylline (114 completing the trial) or placebo (58 completing the trial). The primary efficacy measure was change from baseline to end point in the percentage of daily awake "off" time, recorded by subjects using a patient PD diary. Secondary end points evaluated "on" time (including "on time with dyskinesia"), the Unified Parkinson's Disease Rating Scale, and a Clinical Global Impression-Improvement of Illness score. Clinical laboratory, electrocardiograms, vital signs, and adverse event monitoring comprised the safety monitoring. Results: After randomization, approximately 88% of subjects completed the double-blind period. Compared with baseline, the decrease of daily awake "off' time for istradefylline was a mean (± standard deviation) of -10.8 ± 16.6% (95% confidence interval, -13.46 to -7.52) and for placebo, -4.0 ± 15.7% (95% confidence interval, -7.73-0.31; p = 0.007 using two-way analysis of variance). This effect corresponded to changes from baseline in total daily awake "off' time of -1.8 ± 2.8 hours for istradefylline and -0.6 ± 2.7 hours for placebo (p = 0.005). Treatment-emergent adverse effects with istradefylline were generally mild. 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