Levodopa-Carbidopa Intestinal Gel in Advanced Parkinson'd Disease: Final 12-Month, Open-Label Results
Identifieur interne : 000073 ( Pmc/Corpus ); précédent : 000072; suivant : 000074Levodopa-Carbidopa Intestinal Gel in Advanced Parkinson'd Disease: Final 12-Month, Open-Label Results
Auteurs : Hubert H. Fernandez ; David G. Standaert ; Robert A. Hauser ; Anthony E. Lang ; Victor Sc Fung ; Fabian Klostermann ; Mark F. Lew ; Per Odin ; Malcolm Steiger ; Eduard Z. Yakupov ; Sylvain Chouinard ; Oksana Suchowersky ; Jordan Dubow ; Coleen M. Hall ; Krai Chatamra ; Weining Z. Robieson ; Janet A. Benesh ; Alberto J. EspaySource :
- Movement Disorders [ 0885-3185 ] ; 2014.
Abstract
Motor complications in Parkinson's disease (PD) are associated with long-term oral levodopa treatment and linked to pulsatile dopaminergic stimulation.
Url:
DOI: 10.1002/mds.26123
PubMed: 25545465
PubMed Central: 4674978
Links to Exploration step
PMC:4674978Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Levodopa-Carbidopa Intestinal Gel in Advanced Parkinson'd Disease: Final 12-Month, Open-Label Results</title><author><name sortKey="Fernandez, Hubert H" sort="Fernandez, Hubert H" uniqKey="Fernandez H" first="Hubert H" last="Fernandez">Hubert H. Fernandez</name><affiliation><nlm:aff id="au1"><institution>Center for Neurological Restoration, Cleveland Clinic</institution><addr-line>Cleveland, Ohio, USA</addr-line></nlm:aff></affiliation></author><author><name sortKey="Standaert, David G" sort="Standaert, David G" uniqKey="Standaert D" first="David G" last="Standaert">David G. Standaert</name><affiliation><nlm:aff id="au2"><institution>University of Alabama at Birmingham</institution><addr-line>Birmingham, Alabama, USA</addr-line></nlm:aff></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><nlm:aff id="au3"><institution>Department of Neurology, University of South Florida</institution><addr-line>Tampa, Florida, USA</addr-line></nlm:aff></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><nlm:aff id="au4"><institution>University of Toronto</institution><addr-line>Toronto, Ontario, Canada</addr-line></nlm:aff></affiliation></author><author><name sortKey="Fung, Victor Sc" sort="Fung, Victor Sc" uniqKey="Fung V" first="Victor Sc" last="Fung">Victor Sc Fung</name><affiliation><nlm:aff id="au5"><institution>Movement Disorders Unit, Westmead Hospital and Sydney Medical School</institution><addr-line>Sydney, Australia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Klostermann, Fabian" sort="Klostermann, Fabian" uniqKey="Klostermann F" first="Fabian" last="Klostermann">Fabian Klostermann</name><affiliation><nlm:aff id="au6"><institution>Charité-University Medicine Berlin</institution><addr-line>Berlin, Germany</addr-line></nlm:aff></affiliation></author><author><name sortKey="Lew, Mark F" sort="Lew, Mark F" uniqKey="Lew M" first="Mark F" last="Lew">Mark F. Lew</name><affiliation><nlm:aff id="au7"><institution>Keck/USC School of Medicine</institution><addr-line>Los Angeles, California, USA</addr-line></nlm:aff></affiliation></author><author><name sortKey="Odin, Per" sort="Odin, Per" uniqKey="Odin P" first="Per" last="Odin">Per Odin</name><affiliation><nlm:aff id="au8"><institution>Klinikum-Bremerhaven, Bremerhaven, Germany and Skane University Hospital</institution><addr-line>Lund, Sweden</addr-line></nlm:aff></affiliation></author><author><name sortKey="Steiger, Malcolm" sort="Steiger, Malcolm" uniqKey="Steiger M" first="Malcolm" last="Steiger">Malcolm Steiger</name><affiliation><nlm:aff id="au9"><institution>Walton Center for Neurology and Neurosurgery</institution><addr-line>Liverpool, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Yakupov, Eduard Z" sort="Yakupov, Eduard Z" uniqKey="Yakupov E" first="Eduard Z" last="Yakupov">Eduard Z. Yakupov</name><affiliation><nlm:aff id="au10"><institution>Kazan State Medical University</institution><addr-line>Kazan, Russia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Chouinard, Sylvain" sort="Chouinard, Sylvain" uniqKey="Chouinard S" first="Sylvain" last="Chouinard">Sylvain Chouinard</name><affiliation><nlm:aff id="au11"><institution>University of Montreal</institution><addr-line>Montreal, Quebec, Canada</addr-line></nlm:aff></affiliation></author><author><name sortKey="Suchowersky, Oksana" sort="Suchowersky, Oksana" uniqKey="Suchowersky O" first="Oksana" last="Suchowersky">Oksana Suchowersky</name><affiliation><nlm:aff id="au12"><institution>University of Alberta</institution><addr-line>Edmonton, Alberta, Canada</addr-line></nlm:aff></affiliation></author><author><name sortKey="Dubow, Jordan" sort="Dubow, Jordan" uniqKey="Dubow J" first="Jordan" last="Dubow">Jordan Dubow</name><affiliation><nlm:aff id="au13"><institution>AbbVie Inc., North Chicago</institution><addr-line>Illinois, USA</addr-line></nlm:aff></affiliation></author><author><name sortKey="Hall, Coleen M" sort="Hall, Coleen M" uniqKey="Hall C" first="Coleen M" last="Hall">Coleen M. Hall</name><affiliation><nlm:aff id="au13"><institution>AbbVie Inc., North Chicago</institution><addr-line>Illinois, USA</addr-line></nlm:aff></affiliation></author><author><name sortKey="Chatamra, Krai" sort="Chatamra, Krai" uniqKey="Chatamra K" first="Krai" last="Chatamra">Krai Chatamra</name><affiliation><nlm:aff id="au13"><institution>AbbVie Inc., North Chicago</institution><addr-line>Illinois, USA</addr-line></nlm:aff></affiliation></author><author><name sortKey="Robieson, Weining Z" sort="Robieson, Weining Z" uniqKey="Robieson W" first="Weining Z" last="Robieson">Weining Z. Robieson</name><affiliation><nlm:aff id="au13"><institution>AbbVie Inc., North Chicago</institution><addr-line>Illinois, USA</addr-line></nlm:aff></affiliation></author><author><name sortKey="Benesh, Janet A" sort="Benesh, Janet A" uniqKey="Benesh J" first="Janet A" last="Benesh">Janet A. Benesh</name><affiliation><nlm:aff id="au13"><institution>AbbVie Inc., North Chicago</institution><addr-line>Illinois, USA</addr-line></nlm:aff></affiliation></author><author><name sortKey="Espay, Alberto J" sort="Espay, Alberto J" uniqKey="Espay A" first="Alberto J" last="Espay">Alberto J. Espay</name><affiliation><nlm:aff id="au14"><institution>University of Cincinnati Academic Health Center</institution><addr-line>Cincinnati, Ohio, USA</addr-line></nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">25545465</idno><idno type="pmc">4674978</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4674978</idno><idno type="RBID">PMC:4674978</idno><idno type="doi">10.1002/mds.26123</idno><date when="2014">2014</date><idno type="wicri:Area/Pmc/Corpus">000073</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000073</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Levodopa-Carbidopa Intestinal Gel in Advanced Parkinson'd Disease: Final 12-Month, Open-Label Results</title><author><name sortKey="Fernandez, Hubert H" sort="Fernandez, Hubert H" uniqKey="Fernandez H" first="Hubert H" last="Fernandez">Hubert H. Fernandez</name><affiliation><nlm:aff id="au1"><institution>Center for Neurological Restoration, Cleveland Clinic</institution><addr-line>Cleveland, Ohio, USA</addr-line></nlm:aff></affiliation></author><author><name sortKey="Standaert, David G" sort="Standaert, David G" uniqKey="Standaert D" first="David G" last="Standaert">David G. Standaert</name><affiliation><nlm:aff id="au2"><institution>University of Alabama at Birmingham</institution><addr-line>Birmingham, Alabama, USA</addr-line></nlm:aff></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><nlm:aff id="au3"><institution>Department of Neurology, University of South Florida</institution><addr-line>Tampa, Florida, USA</addr-line></nlm:aff></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><nlm:aff id="au4"><institution>University of Toronto</institution><addr-line>Toronto, Ontario, Canada</addr-line></nlm:aff></affiliation></author><author><name sortKey="Fung, Victor Sc" sort="Fung, Victor Sc" uniqKey="Fung V" first="Victor Sc" last="Fung">Victor Sc Fung</name><affiliation><nlm:aff id="au5"><institution>Movement Disorders Unit, Westmead Hospital and Sydney Medical School</institution><addr-line>Sydney, Australia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Klostermann, Fabian" sort="Klostermann, Fabian" uniqKey="Klostermann F" first="Fabian" last="Klostermann">Fabian Klostermann</name><affiliation><nlm:aff id="au6"><institution>Charité-University Medicine Berlin</institution><addr-line>Berlin, Germany</addr-line></nlm:aff></affiliation></author><author><name sortKey="Lew, Mark F" sort="Lew, Mark F" uniqKey="Lew M" first="Mark F" last="Lew">Mark F. Lew</name><affiliation><nlm:aff id="au7"><institution>Keck/USC School of Medicine</institution><addr-line>Los Angeles, California, USA</addr-line></nlm:aff></affiliation></author><author><name sortKey="Odin, Per" sort="Odin, Per" uniqKey="Odin P" first="Per" last="Odin">Per Odin</name><affiliation><nlm:aff id="au8"><institution>Klinikum-Bremerhaven, Bremerhaven, Germany and Skane University Hospital</institution><addr-line>Lund, Sweden</addr-line></nlm:aff></affiliation></author><author><name sortKey="Steiger, Malcolm" sort="Steiger, Malcolm" uniqKey="Steiger M" first="Malcolm" last="Steiger">Malcolm Steiger</name><affiliation><nlm:aff id="au9"><institution>Walton Center for Neurology and Neurosurgery</institution><addr-line>Liverpool, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Yakupov, Eduard Z" sort="Yakupov, Eduard Z" uniqKey="Yakupov E" first="Eduard Z" last="Yakupov">Eduard Z. Yakupov</name><affiliation><nlm:aff id="au10"><institution>Kazan State Medical University</institution><addr-line>Kazan, Russia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Chouinard, Sylvain" sort="Chouinard, Sylvain" uniqKey="Chouinard S" first="Sylvain" last="Chouinard">Sylvain Chouinard</name><affiliation><nlm:aff id="au11"><institution>University of Montreal</institution><addr-line>Montreal, Quebec, Canada</addr-line></nlm:aff></affiliation></author><author><name sortKey="Suchowersky, Oksana" sort="Suchowersky, Oksana" uniqKey="Suchowersky O" first="Oksana" last="Suchowersky">Oksana Suchowersky</name><affiliation><nlm:aff id="au12"><institution>University of Alberta</institution><addr-line>Edmonton, Alberta, Canada</addr-line></nlm:aff></affiliation></author><author><name sortKey="Dubow, Jordan" sort="Dubow, Jordan" uniqKey="Dubow J" first="Jordan" last="Dubow">Jordan Dubow</name><affiliation><nlm:aff id="au13"><institution>AbbVie Inc., North Chicago</institution><addr-line>Illinois, USA</addr-line></nlm:aff></affiliation></author><author><name sortKey="Hall, Coleen M" sort="Hall, Coleen M" uniqKey="Hall C" first="Coleen M" last="Hall">Coleen M. Hall</name><affiliation><nlm:aff id="au13"><institution>AbbVie Inc., North Chicago</institution><addr-line>Illinois, USA</addr-line></nlm:aff></affiliation></author><author><name sortKey="Chatamra, Krai" sort="Chatamra, Krai" uniqKey="Chatamra K" first="Krai" last="Chatamra">Krai Chatamra</name><affiliation><nlm:aff id="au13"><institution>AbbVie Inc., North Chicago</institution><addr-line>Illinois, USA</addr-line></nlm:aff></affiliation></author><author><name sortKey="Robieson, Weining Z" sort="Robieson, Weining Z" uniqKey="Robieson W" first="Weining Z" last="Robieson">Weining Z. Robieson</name><affiliation><nlm:aff id="au13"><institution>AbbVie Inc., North Chicago</institution><addr-line>Illinois, USA</addr-line></nlm:aff></affiliation></author><author><name sortKey="Benesh, Janet A" sort="Benesh, Janet A" uniqKey="Benesh J" first="Janet A" last="Benesh">Janet A. Benesh</name><affiliation><nlm:aff id="au13"><institution>AbbVie Inc., North Chicago</institution><addr-line>Illinois, USA</addr-line></nlm:aff></affiliation></author><author><name sortKey="Espay, Alberto J" sort="Espay, Alberto J" uniqKey="Espay A" first="Alberto J" last="Espay">Alberto J. Espay</name><affiliation><nlm:aff id="au14"><institution>University of Cincinnati Academic Health Center</institution><addr-line>Cincinnati, Ohio, USA</addr-line></nlm:aff></affiliation></author></analytic><series><title level="j">Movement Disorders</title><idno type="ISSN">0885-3185</idno><idno type="eISSN">1531-8257</idno><imprint><date when="2014">2014</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Motor complications in Parkinson's disease (PD) are associated with long-term oral levodopa treatment and linked to pulsatile dopaminergic stimulation. <sc>l</sc>-dopa-carbidopa intestinal gel (LCIG) is delivered continuously by percutaneous endoscopic gastrojejunostomy tube (PEG-J), which reduces <sc>l-</sc>dopa-plasma–level fluctuations and can translate to reduced motor complications. We present final results of the largest international, prospective, 54-week, open-label LCIG study. PD patients with severe motor fluctuations (>3 h/day “off” time) despite optimized therapy received LCIG monotherapy. Additional PD medications were allowed >28 days post-LCIG initiation. Safety was the primary endpoint measured through adverse events (AEs), device complications, and number of completers. Secondary endpoints included diary-assessed off time, “on” time with/without troublesome dyskinesia, UPDRS, and health-related quality-of-life (HRQoL) outcomes. Of 354 enrolled patients, 324 (91.5%) received PEG-J and 272 (76.8%) completed the study. Most AEs were mild/moderate and transient; complication of device insertion (34.9%) was the most common. Twenty-seven (7.6%) patients withdrew because of AEs. Serious AEs occurred in 105 (32.4%), most commonly complication of device insertion (6.5%). Mean daily off time decreased by 4.4 h/65.6% (<italic>P</italic> < 0.001). On time without troublesome dyskinesia increased by 4.8 h/62.9% (<italic>P</italic> < 0.001); on time with troublesome dyskinesia decreased by 0.4 h/22.5% (<italic>P</italic> = 0.023). Improvements persisted from week 4 through study completion. UPDRS and HRQoL outcomes were also improved throughout. In the advanced PD population, LCIG's safety profile consisted primarily of AEs associated with the device/procedure, <sc>l-</sc>dopa/carbidopa, and advanced PD. LCIG was generally well tolerated and demonstrated clinically significant improvements in motor function, daily activities, and HRQoL sustained over 54 weeks. © 2014 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Hauser, Ra" uniqKey="Hauser R">RA Hauser</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Hornykiewicz, O" uniqKey="Hornykiewicz O">O Hornykiewicz</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Lundqvist, C" uniqKey="Lundqvist C">C Lundqvist</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Antonini, A" uniqKey="Antonini A">A Antonini</name></author><author><name sortKey="Chaudhuri, Kr" uniqKey="Chaudhuri K">KR Chaudhuri</name></author><author><name sortKey="Martinez Martin, P" uniqKey="Martinez Martin P">P Martinez-Martin</name></author><author><name sortKey="Odin, P" uniqKey="Odin P">P 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article-type="research-article"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Mov Disord</journal-id><journal-id journal-id-type="iso-abbrev">Mov. Disord</journal-id><journal-id journal-id-type="publisher-id">mds</journal-id><journal-title-group><journal-title>Movement Disorders</journal-title></journal-title-group><issn pub-type="ppub">0885-3185</issn><issn pub-type="epub">1531-8257</issn><publisher><publisher-name>Blackwell Publishing Ltd</publisher-name><publisher-loc>Oxford, UK</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">25545465</article-id><article-id pub-id-type="pmc">4674978</article-id><article-id pub-id-type="doi">10.1002/mds.26123</article-id><article-categories><subj-group subj-group-type="heading"><subject>Research Articles</subject></subj-group></article-categories><title-group><article-title>Levodopa-Carbidopa Intestinal Gel in Advanced Parkinson'd Disease: Final 12-Month, Open-Label Results</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Fernandez</surname><given-names>Hubert H</given-names></name><degrees>MD</degrees><xref ref-type="aff" rid="au1">1</xref><xref ref-type="corresp" rid="cor1">*</xref></contrib><contrib contrib-type="author"><name><surname>Standaert</surname><given-names>David G</given-names></name><degrees>MD, PhD</degrees><xref ref-type="aff" rid="au2">2</xref></contrib><contrib contrib-type="author"><name><surname>Hauser</surname><given-names>Robert A</given-names></name><degrees>MD</degrees><xref ref-type="aff" rid="au3">3</xref></contrib><contrib contrib-type="author"><name><surname>Lang</surname><given-names>Anthony E</given-names></name><degrees>MD, FRCPC</degrees><xref ref-type="aff" rid="au4">4</xref></contrib><contrib contrib-type="author"><name><surname>Fung</surname><given-names>Victor SC</given-names></name><degrees>PhD, FRACP</degrees><xref ref-type="aff" rid="au5">5</xref></contrib><contrib contrib-type="author"><name><surname>Klostermann</surname><given-names>Fabian</given-names></name><degrees>PhD</degrees><xref ref-type="aff" rid="au6">6</xref></contrib><contrib contrib-type="author"><name><surname>Lew</surname><given-names>Mark F</given-names></name><degrees>MD</degrees><xref ref-type="aff" rid="au7">7</xref></contrib><contrib contrib-type="author"><name><surname>Odin</surname><given-names>Per</given-names></name><degrees>MD, PhD</degrees><xref ref-type="aff" rid="au8">8</xref></contrib><contrib contrib-type="author"><name><surname>Steiger</surname><given-names>Malcolm</given-names></name><degrees>MBBS, MD, FRCP</degrees><xref ref-type="aff" rid="au9">9</xref></contrib><contrib contrib-type="author"><name><surname>Yakupov</surname><given-names>Eduard Z</given-names></name><degrees>MD, PhD, DMSc</degrees><xref ref-type="aff" rid="au10">10</xref></contrib><contrib contrib-type="author"><name><surname>Chouinard</surname><given-names>Sylvain</given-names></name><degrees>MD, FRCPC</degrees><xref ref-type="aff" rid="au11">11</xref></contrib><contrib contrib-type="author"><name><surname>Suchowersky</surname><given-names>Oksana</given-names></name><degrees>MD, FRCPC, FCCMG</degrees><xref ref-type="aff" rid="au12">12</xref></contrib><contrib contrib-type="author"><name><surname>Dubow</surname><given-names>Jordan</given-names></name><degrees>MD</degrees><xref ref-type="aff" rid="au13">13</xref></contrib><contrib contrib-type="author"><name><surname>Hall</surname><given-names>Coleen M</given-names></name><degrees>MS</degrees><xref ref-type="aff" rid="au13">13</xref></contrib><contrib contrib-type="author"><name><surname>Chatamra</surname><given-names>Krai</given-names></name><degrees>PhD</degrees><xref ref-type="aff" rid="au13">13</xref></contrib><contrib contrib-type="author"><name><surname>Robieson</surname><given-names>Weining Z</given-names></name><degrees>PhD</degrees><xref ref-type="aff" rid="au13">13</xref></contrib><contrib contrib-type="author"><name><surname>Benesh</surname><given-names>Janet A</given-names></name><degrees>BSMT</degrees><xref ref-type="aff" rid="au13">13</xref></contrib><contrib contrib-type="author"><name><surname>Espay</surname><given-names>Alberto J</given-names></name><degrees>MD, MSc</degrees><xref ref-type="aff" rid="au14">14</xref></contrib><aff id="au1"><label>1</label><institution>Center for Neurological Restoration, Cleveland Clinic</institution><addr-line>Cleveland, Ohio, USA</addr-line></aff><aff id="au2"><label>2</label><institution>University of Alabama at Birmingham</institution><addr-line>Birmingham, Alabama, USA</addr-line></aff><aff id="au3"><label>3</label><institution>Department of Neurology, University of South Florida</institution><addr-line>Tampa, Florida, USA</addr-line></aff><aff id="au4"><label>4</label><institution>University of Toronto</institution><addr-line>Toronto, Ontario, Canada</addr-line></aff><aff id="au5"><label>5</label><institution>Movement Disorders Unit, Westmead Hospital and Sydney Medical School</institution><addr-line>Sydney, Australia</addr-line></aff><aff id="au6"><label>6</label><institution>Charité-University Medicine Berlin</institution><addr-line>Berlin, Germany</addr-line></aff><aff id="au7"><label>7</label><institution>Keck/USC School of Medicine</institution><addr-line>Los Angeles, California, USA</addr-line></aff><aff id="au8"><label>8</label><institution>Klinikum-Bremerhaven, Bremerhaven, Germany and Skane University Hospital</institution><addr-line>Lund, Sweden</addr-line></aff><aff id="au9"><label>9</label><institution>Walton Center for Neurology and Neurosurgery</institution><addr-line>Liverpool, United Kingdom</addr-line></aff><aff id="au10"><label>10</label><institution>Kazan State Medical University</institution><addr-line>Kazan, Russia</addr-line></aff><aff id="au11"><label>11</label><institution>University of Montreal</institution><addr-line>Montreal, Quebec, Canada</addr-line></aff><aff id="au12"><label>12</label><institution>University of Alberta</institution><addr-line>Edmonton, Alberta, Canada</addr-line></aff><aff id="au13"><label>13</label><institution>AbbVie Inc., North Chicago</institution><addr-line>Illinois, USA</addr-line></aff><aff id="au14"><label>14</label><institution>University of Cincinnati Academic Health Center</institution><addr-line>Cincinnati, Ohio, USA</addr-line></aff></contrib-group><author-notes><corresp id="cor1">*<bold>Correspondence to</bold>: Dr. Hubert H. Fernandez, Center for Neurological Restoration, Cleveland Clinic, 9500 Euclid Avenue, U-2, Cleveland, OH 44195, USA; <email>fernanh@ccf.org</email> or Dr. David G. Standaert, Department of Neurology, 1719 6th Avenue South, CIRC 516, Birmingham, AL 35294, USA; <email>dstandaert@uab.edu</email></corresp><fn><p><bold>Funding agencies:</bold> This study was sponsored by AbbVie Inc. (North Chicago, IL, USA), which participated in the study design, research, data collection, analysis and interpretation of data, writing, reviewing, and approving the publication. Funding for editorial and graphic support was provided by AbbVie Inc. to The Curry Rockefeller Group, LLC; medical writing assistance was provided by Michael Feirtag, Susan Kralian, PhD, Paul V. Shea, Jennifer Kuo, PharmD, and John Norwood of The Curry Rockefeller Group, LLC.</p></fn><fn><p><bold>Relevant conflicts of interest/financial disclosures:</bold> H.H.F. was a study investigator and has served as a consultant for AbbVie Inc. through a contract between AbbVie Inc. and Cleveland Clinic Foundation; he has not received any personal compensation from AbbVie Inc. D.G.S. was a study investigator for, and has received compensation from, AbbVie Inc. for serving as a consultant and/or participating in scientific advisory boards. R.A.H. was a study investigator for AbbVie Inc. and has received honoraria or payments for consulting, advisory services, or speaking services over the past 12 months from AbbVie Inc. A.E.L. was a study investigator for AbbVie Inc. and has received compensation from AbbVie Inc. for participating in scientific advisory boards. V.S.C.F. was a study investigator for, and has also received compensation from, AbbVie Inc. for participating in scientific advisory boards; AbbVie Inc. contributed to funding for a Parkinson's disease nurse specialist in the form of a grant to his institution. F.K. was a study investigator for, and has received compensation from, AbbVie Inc. for participating in scientific advisory boards and for serving as a lecturer. M.F.L. was a study investigator for AbbVie Inc. P.O. was a study investigator in AbbVie Inc.-sponsored studies and has received compensation from AbbVie Inc. for serving as a consultant and lecturer. M.S. was a study investigator in AbbVie Inc.-sponsored studies and has received compensation from AbbVie Inc. for participating in scientific advisory boards. E.Z.Y. was a study investigator for, and has received compensation from, AbbVie Inc. for serving as a lecturer. S.C. was a study investigator for, and has received compensation from, AbbVie Inc. for serving as a consultant, lecturer, and/or participating in scientific advisory boards. O.S. was a study investigator for, and has received compensation from, AbbVie Inc. for serving as a consultant and/or participating in scientific advisory boards. J.D., C.M.H., K.C., W.Z.R., and J.A.B. are employees of AbbVie Inc. A.J.E. was a study investigator for, and has received compensation from, AbbVie Inc. for serving as a consultant, lecturer, and/or participating in scientific advisory boards.</p></fn><fn><p>Full financial disclosures and author roles may be found in the online version of this article.</p></fn></author-notes><pub-date pub-type="ppub"><month>4</month><year>2015</year></pub-date><pub-date pub-type="epub"><day>24</day><month>12</month><year>2014</year></pub-date><volume>30</volume><issue>4</issue><fpage>500</fpage><lpage>509</lpage><history><date date-type="received"><day>28</day><month>8</month><year>2014</year></date><date date-type="rev-recd"><day>07</day><month>11</month><year>2014</year></date><date date-type="accepted"><day>18</day><month>11</month><year>2014</year></date></history><permissions><copyright-statement>© 2014 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.</copyright-statement><copyright-year>2014</copyright-year><license license-type="open-access" xlink:href="http://creativecommons.org/licenses/by/4.0/"><license-p>This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.</license-p></license></permissions><abstract><p>Motor complications in Parkinson's disease (PD) are associated with long-term oral levodopa treatment and linked to pulsatile dopaminergic stimulation. <sc>l</sc>-dopa-carbidopa intestinal gel (LCIG) is delivered continuously by percutaneous endoscopic gastrojejunostomy tube (PEG-J), which reduces <sc>l-</sc>dopa-plasma–level fluctuations and can translate to reduced motor complications. We present final results of the largest international, prospective, 54-week, open-label LCIG study. PD patients with severe motor fluctuations (>3 h/day “off” time) despite optimized therapy received LCIG monotherapy. Additional PD medications were allowed >28 days post-LCIG initiation. Safety was the primary endpoint measured through adverse events (AEs), device complications, and number of completers. Secondary endpoints included diary-assessed off time, “on” time with/without troublesome dyskinesia, UPDRS, and health-related quality-of-life (HRQoL) outcomes. Of 354 enrolled patients, 324 (91.5%) received PEG-J and 272 (76.8%) completed the study. Most AEs were mild/moderate and transient; complication of device insertion (34.9%) was the most common. Twenty-seven (7.6%) patients withdrew because of AEs. Serious AEs occurred in 105 (32.4%), most commonly complication of device insertion (6.5%). Mean daily off time decreased by 4.4 h/65.6% (<italic>P</italic> < 0.001). On time without troublesome dyskinesia increased by 4.8 h/62.9% (<italic>P</italic> < 0.001); on time with troublesome dyskinesia decreased by 0.4 h/22.5% (<italic>P</italic> = 0.023). Improvements persisted from week 4 through study completion. UPDRS and HRQoL outcomes were also improved throughout. In the advanced PD population, LCIG's safety profile consisted primarily of AEs associated with the device/procedure, <sc>l-</sc>dopa/carbidopa, and advanced PD. LCIG was generally well tolerated and demonstrated clinically significant improvements in motor function, daily activities, and HRQoL sustained over 54 weeks. © 2014 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.</p></abstract><kwd-group><kwd>dyskinesia</kwd><kwd>infusion</kwd><kwd>levodopa-carbidopa intestinal gel</kwd><kwd>“off” time</kwd><kwd>percutaneous endoscopic gastrojejunostomy</kwd></kwd-group></article-meta></front><body><p>Oral levodopa (<sc>L</sc>-dopa) is one of the most effective therapies for Parkinson's disease (PD).<xref rid="b1" ref-type="bibr">1</xref>–<xref rid="b4" ref-type="bibr">4</xref> During early disease stage, motor symptoms are well controlled with 3 to 4 daily doses. As PD progresses, however, oral <sc>l-</sc>dopa's effect may not be sustained between doses and symptoms may re-emerge.<xref rid="b3" ref-type="bibr">3</xref>–<xref rid="b6" ref-type="bibr">6</xref> Adjunctive therapies may initially reduce the duration of motor complications (i.e., decrease “off” time by approximately 1-2 hours per day); however, dyskinesia and other adverse events (AEs) increase.<xref rid="b7" ref-type="bibr">7</xref>–<xref rid="b9" ref-type="bibr">9</xref> Oral <sc>l-</sc>dopa pharmacokinetic properties contribute to oscillations in plasma <sc>l-</sc>dopa levels,<xref rid="b3" ref-type="bibr">3</xref>–<xref rid="b5" ref-type="bibr">5</xref> which may be compounded by variability of gastric emptying and <sc>l-</sc>dopa absorption.<xref rid="b10" ref-type="bibr">10</xref>,<xref rid="b11" ref-type="bibr">11</xref></p><p>Establishing stable plasma <sc>l-</sc>dopa levels may provide more continuous dopaminergic stimulation, resulting in decreased motor fluctuations.<xref rid="b4" ref-type="bibr">4</xref>,<xref rid="b6" ref-type="bibr">6</xref><sc>l-</sc>dopa-carbidopa intestinal gel (LCIG) offers continuous drug delivery and may provide a closer approximation of physiological continuous dopaminergic stimulation through its amelioration of plasma-level fluctuations, including the depth and frequency of serum troughs.<xref rid="b5" ref-type="bibr">5</xref> LCIG is delivered continuously by portable pump through a percutaneous endoscopic gastrojejunostomy (PEG-J) tube,<xref rid="b1" ref-type="bibr">1</xref>,<xref rid="b6" ref-type="bibr">6</xref>,<xref rid="b12" ref-type="bibr">12</xref> bypassing the stomach to eliminate variability associated with gastric emptying,<xref rid="b4" ref-type="bibr">4</xref>,<xref rid="b10" ref-type="bibr">10</xref> resulting in a significant decrease in off time duration.<xref rid="b5" ref-type="bibr">5</xref>,<xref rid="b12" ref-type="bibr">12</xref>–<xref rid="b15" ref-type="bibr">15</xref></p><p>The efficacy of LCIG as an adjunctive therapy was evaluated in a double-blind, double-dummy, phase III study, which showed a 4.0-hour reduction from baseline in off time among patients randomized to LCIG and a 1.9-hour difference in off time reduction versus optimized oral <sc>l-</sc>dopa (<italic>P</italic> = 0.0015).<xref rid="b15" ref-type="bibr">15</xref> Previous open-label studies also showed statistically significant reductions in off time and/or dyskinesia versus baseline.<xref rid="b13" ref-type="bibr">13</xref>,<xref rid="b14" ref-type="bibr">14</xref>,<xref rid="b16" ref-type="bibr">16</xref>–<xref rid="b21" ref-type="bibr">21</xref> However, these studies were small by design, comprised of 5 to 91 patients. This large study was designed to provide needed longer-term safety and efficacy results with clinical applicability to an international patient population with advanced PD. Furthermore, the study investigated the initiation and maintenance of LCIG as monotherapy, replacing adjunctive PD therapy.</p><sec sec-type="methods"><title>Patients and Methods</title><p>The safety and efficacy of LCIG were evaluated in patients with advanced PD experiencing motor fluctuations despite optimized medical therapy in an open-label, phase III, 12-month study (<ext-link ext-link-type="uri" xlink:href="http://ClinicalTrials.gov">http://ClinicalTrials.gov</ext-link>: NCT00335153). The study methodology has been reported on<xref rid="b22" ref-type="bibr">22</xref> and is summarized below. The study protocol was approved by the institutional review board/ethics committee at all 86 centers in 16 countries. All patients provided written informed consent.</p><sec><title>Study Design</title><p>The study included a screening period (≤28 days), baseline assessments, a nasojejunal (NJ) titration period (2-14 days), a PEG-J titration period (2-14 days), and a 54-week treatment period (<xref ref-type="fig" rid="fig01">Fig. 1</xref>A). The starting infusion dose was based on each patient's previous daily dose of oral <sc>l-</sc>dopa. Usage of other PD medications that required tapering off was compensated for at the investigator's discretion. Patients were hospitalized for NJ tube placement and initiation of LCIG titration as well as PEG-J tube placement and further dose optimization by PEG-J, if required. At the end of titration, patients entered long-term PEG-J treatment and assessments began on day 28. LCIG was administered by a portable pump during waking hours; a morning dose/bolus was followed by continuous infusion for approximately 16 hours with additional rescue doses during the day, if clinically indicated. The use of oral immediate-release <sc>l-</sc>dopa-carbidopa was permitted only when the pump was turned off at night. Use of other PD medications was permitted after 28 days post-LCIG initiation at the investigator's discretion. Apomorphine and controlled-release <sc>l-</sc>dopa-carbidopa were not permitted.</p><fig id="fig01" position="float"><label>Fig. 1</label><caption><p>(A) Study design. (B) Patient disposition.</p></caption><graphic xlink:href="mds0030-0500-f1"></graphic></fig><p>Safety and tolerability provided the primary endpoint whereas efficacy assessments provided the secondary endpoints.</p></sec><sec sec-type="methods"><title>Patients</title><p>Eligible patients were ≥30 years old, <sc>l-</sc>dopa responsive, met UK Parkinson's Disease Society Brain Bank diagnostic criteria, and had severe motor fluctuations defined as ≥3 hours of daily off time at baseline (confirmed by the PD symptom diary), despite optimized treatment with available PD medications.</p></sec><sec><title>Safety</title><p>Safety measures included AEs, infusion device complications, and tolerability assessed by number of patients completing the study. Laboratory results, vital signs, and electrocardiogram (ECG) were monitored.</p><p>AEs were coded according to Medical Dictionary for Regulatory Activities (MedDRA) version 14.0. Each event could be coded to one or more terms descriptive of the event. Planned hospitalization for baseline assessment and treatment initiation was not considered a serious AE (SAE) unless hospitalization was prolonged as a result of complications. All AEs reported are treatment-emergent AEs, which were defined as those that began or worsened from the time of NJ tube insertion until 30 days after PEG-J removal. AEs of special interest were monitored. These were AEs associated with neuropathy, the procedure and device (e.g., PEG-J placement), respiratory tract aspiration, weight loss, and cardiovascular fatalities.</p></sec><sec><title>Efficacy</title><p>Efficacy outcomes included assessed mean change from baseline to last visit in patient-diary off time, “on” time with troublesome dyskinesia, and on time without troublesome dyskinesia (on time without dyskinesia plus on time with nontroublesome dyskinesia, i.e., does not interfere with function or cause meaningful discomfort); the investigator-rated Clinical Global Impression-Improvement (CGI-I) scale; the UPDRS<xref rid="b23" ref-type="bibr">23</xref> Parts II, III, total score (Parts I–III), and the dyskinesia items from Part IV (questions 32-34); the 39-item PD Questionnaire (PDQ-39)<xref rid="b24" ref-type="bibr">24</xref>; the EuroQoL-5D (EQ-5D) Summary Index<xref rid="b25" ref-type="bibr">25</xref>; and the EuroQoL visual analog scale (EQ-VAS).<xref rid="b26" ref-type="bibr">26</xref> Efficacy assessments were collected during post-PEG-J weeks 4, 12, 24, and 54; PD diary and CGI-I were also collected at post-PEG-J week 36. PDQ-39 was administered during screening visit 1 rather than at baseline.</p><p>Patients were trained to record their motor states every 30 minutes throughout the waking day using a 24-hour diary (Hauser diary)<xref rid="b27" ref-type="bibr">27</xref> over the 3 consecutive days preceding baseline and each scheduled visit. PD diary variables were normalized to a 16-hour waking day and averaged over the 3 consecutive days. At baseline, clinicians rated the severity of patients' symptoms with the Clinical Global Impression-Severity (CGI-S) scale. During treatment, clinicians used the CGI-I scale. The UPDRS was administered by the investigator during the best on state (usually 2-4 hours after the morning dose).</p></sec><sec><title>Statistical Analyses</title><p>Efficacy analyses included all patients who received LCIG during the post-PEG-J period and completed ≥1 postbaseline efficacy assessment. Safety analysis included all patients who had NJ placement and completed ≥1 postbaseline safety evaluation. The within-group magnitude of change for all efficacy outcome measures was tested using a one-sample <italic>t</italic> test. Multiple testing procedures were not used to control for study-wise type I error rate. Planned enrollment was 320 patients to provide a sufficient sample to satisfy regulatory requirements for exposure assessments at 6 and 12 months.</p></sec></sec><sec sec-type="results"><title>Results</title><sec><title>Patient Disposition and Baseline Measures</title><p>Of 354 enrolled patients, 324 (91.5%) completed the NJ phase and 272 completed the study (76.8% of all patients enrolled, 84.0% of those who proceeded to PEG-J treatment; <xref ref-type="fig" rid="fig01">Fig. 1</xref>B).</p><p>Eighty-two patients (23.2%) prematurely discontinued, of whom 27 (7.6%) discontinued as the result of an AE. Other reasons for withdrawal were administrative reasons (4.0%; e.g., protocol-specified discontinuations for timely study closure), major protocol violations (2.5%), lack of efficacy (2.0%), and withdrawal of consent (7.1%; reasons for withdrawal of consent were not collected).</p><p>At baseline, patients had a mean ± standard deviation (SD) age of 64.1 ± 9.1 years, PD duration of 12.5 ± 5.5 years, and off time of 6.75 ± 2.35 hours per day (Table <xref ref-type="table" rid="tbl1">1</xref>). Ninety-four patients (26.6%) were on <sc>l-</sc>dopa (or <sc>l-</sc>dopa derivative) monotherapy, whereas 259 (73.2%) were receiving ≥2 PD medications (including <sc>l-</sc>dopa for all patients) in any combination (primarily dopamine agonists [55.4% of all patients], amantadine [29.9%], and catechol-<italic>O</italic>-methyltransferase (COMT) inhibitors [28.2%]), all of which were discontinued before LCIG treatment.</p><table-wrap id="tbl1" position="float"><label>TABLE 1</label><caption><p>Baseline characteristics (n = 354)</p></caption><table frame="hsides" rules="groups"><thead><tr><th align="left" rowspan="1" colspan="1">Characteristic</th><th align="center" rowspan="1" colspan="1">Value</th></tr></thead><tbody><tr><td align="left" rowspan="1" colspan="1">Age, years</td><td rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"> Mean ± SD</td><td align="center" rowspan="1" colspan="1">64.1 ± 9.1</td></tr><tr><td align="left" rowspan="1" colspan="1">Sex, males, n (%)</td><td align="center" rowspan="1" colspan="1">202 (57.1)</td></tr><tr><td align="left" rowspan="1" colspan="1">Race, n (%)</td><td rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"> White</td><td align="center" rowspan="1" colspan="1">328 (92.7)</td></tr><tr><td align="left" rowspan="1" colspan="1"> Asian</td><td align="center" rowspan="1" colspan="1">22 (6.2)</td></tr><tr><td align="left" rowspan="1" colspan="1"> Black</td><td align="center" rowspan="1" colspan="1">4 (1.1)</td></tr><tr><td align="left" rowspan="1" colspan="1">Weight, kg</td><td rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"> Mean ± SD</td><td align="center" rowspan="1" colspan="1">70.8 ± 15.8</td></tr><tr><td align="left" rowspan="1" colspan="1"> Median (range)</td><td align="center" rowspan="1" colspan="1">69.5 (39.7-123.0)</td></tr><tr><td align="left" rowspan="1" colspan="1">PD duration in years, mean ± SD</td><td align="center" rowspan="1" colspan="1">12.5 ± 5.5</td></tr><tr><td align="left" rowspan="1" colspan="1"><sc>l</sc>-dopa dose at screening, mg/day, mean ± SD</td><td align="center" rowspan="1" colspan="1">1,082.9 ± 582.1</td></tr><tr><td align="left" rowspan="1" colspan="1">PD medications, n (%)<xref ref-type="table-fn" rid="tf1-1">a</xref></td><td rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"> Number of PD medication classes received</td><td rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"> One (all <sc>l</sc>-dopa or derivative alone)</td><td align="center" rowspan="1" colspan="1">94 (26.6)</td></tr><tr><td align="left" rowspan="1" colspan="1"> Two</td><td align="center" rowspan="1" colspan="1">112 (31.6)</td></tr><tr><td align="left" rowspan="1" colspan="1"> Three</td><td align="center" rowspan="1" colspan="1">87 (24.6)</td></tr><tr><td align="left" rowspan="1" colspan="1"> More than three</td><td align="center" rowspan="1" colspan="1">60 (16.9)</td></tr><tr><td align="left" rowspan="1" colspan="1"> Medication classes of those receiving ≥2 PD medications</td><td rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"> <sc>l</sc>-dopa or derivatives</td><td align="center" rowspan="1" colspan="1">259 (73.2)</td></tr><tr><td align="left" rowspan="1" colspan="1"> Dopamine agonists</td><td align="center" rowspan="1" colspan="1">196 (55.4)</td></tr><tr><td align="left" rowspan="1" colspan="1"> COMT inhibitors</td><td align="center" rowspan="1" colspan="1">100 (28.2)</td></tr><tr><td align="left" rowspan="1" colspan="1"> Amantadine</td><td align="center" rowspan="1" colspan="1">106 (29.9)</td></tr><tr><td align="left" rowspan="1" colspan="1"> MAO-B inhibitors</td><td align="center" rowspan="1" colspan="1">45 (12.7)</td></tr><tr><td align="left" rowspan="1" colspan="1"> Tertiary amines</td><td align="center" rowspan="1" colspan="1">11 (3.1)</td></tr><tr><td align="left" rowspan="1" colspan="1"> Not recorded</td><td align="center" rowspan="1" colspan="1">1 (0.3)</td></tr><tr><td align="left" rowspan="1" colspan="1">Off time in hours/day,<xref ref-type="table-fn" rid="tf1-2">b</xref> mean ± SD</td><td align="center" rowspan="1" colspan="1">6.75 ± 2.35</td></tr><tr><td align="left" rowspan="1" colspan="1">On time without troublesome dyskinesia in hours/day,<xref ref-type="table-fn" rid="tf1-2">b</xref> mean ± SD</td><td align="center" rowspan="1" colspan="1">7.65 ± 2.45</td></tr><tr><td align="left" rowspan="1" colspan="1">On time with troublesome dyskinesia in hours/day,<xref ref-type="table-fn" rid="tf1-2">b</xref> mean ± SD</td><td align="center" rowspan="1" colspan="1">1.61 ± 2.03</td></tr><tr><td align="left" rowspan="1" colspan="1">CGI-S scale,<xref ref-type="table-fn" rid="tf1-2">b</xref>,<xref ref-type="table-fn" rid="tf1-3">c</xref> mean ± SD</td><td align="center" rowspan="1" colspan="1">4.85 ± 0.84</td></tr><tr><td align="left" rowspan="1" colspan="1">UPDRS scores,<xref ref-type="table-fn" rid="tf1-4">d</xref> mean ± SD</td><td rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"> Total (sum of Parts I, II and III)<xref ref-type="table-fn" rid="tf1-5">e</xref></td><td align="center" rowspan="1" colspan="1">48.4 ± 18.9</td></tr><tr><td align="left" rowspan="1" colspan="1"> Part II (activities of daily living)<xref ref-type="table-fn" rid="tf1-6">f</xref></td><td align="center" rowspan="1" colspan="1">17.4 ± 6.6</td></tr><tr><td align="left" rowspan="1" colspan="1"> Part III (motor symptoms)<xref ref-type="table-fn" rid="tf1-7">g</xref></td><td align="center" rowspan="1" colspan="1">28.8 ± 13.7</td></tr><tr><td align="left" rowspan="1" colspan="1"> Part IV (dyskinesia items nos. 32, 33 and 34 only)<xref ref-type="table-fn" rid="tf1-5">e</xref></td><td align="center" rowspan="1" colspan="1">3.7 ± 2.4</td></tr><tr><td align="left" rowspan="1" colspan="1">PDQ-39 Summary Index score,<xref ref-type="table-fn" rid="tf1-8">h</xref> mean ± SD</td><td align="center" rowspan="1" colspan="1">42.8 ± 15.1</td></tr><tr><td align="left" rowspan="1" colspan="1">EQ-5D Summary Index score,<xref ref-type="table-fn" rid="tf1-9">i</xref> mean ± SD</td><td align="center" rowspan="1" colspan="1">0.588 ± 0.195</td></tr><tr><td align="left" rowspan="1" colspan="1">EQ-VAS score,<xref ref-type="table-fn" rid="tf1-9">i</xref> mean ± SD</td><td align="center" rowspan="1" colspan="1">50.2 ± 21.0</td></tr></tbody></table><table-wrap-foot><fn id="tf1-1"><label>a</label><p>Some patients' medications were tapered and discontinued before baseline; listed drug categories are those used by ≥3.0% of all patients.</p></fn><fn id="tf1-2"><label>b</label><p>n = 316.</p></fn><fn id="tf1-3"><label>c</label><p>The CGI-S is a 7-point Likert scale ranging from 1 (normal) to 7 (most ill).</p></fn><fn id="tf1-4"><label>d</label><p>Higher UPDRS scores are associated with more disability.</p></fn><fn id="tf1-5"><label>e</label><p>n = 292.</p></fn><fn id="tf1-6"><label>f</label><p>n = 293.</p></fn><fn id="tf1-7"><label>g</label><p>n = 291.</p></fn><fn id="tf1-8"><label>h</label><p>n = 320; Higher PDQ-39 scores are associated with more severe symptoms.</p></fn><fn id="tf1-9"><label>i</label><p>n = 318; Higher EQ scores are associated with better health.</p></fn></table-wrap-foot></table-wrap></sec><sec><title>Total Daily <sc>l-</sc>dopa Dose</title><p>All patients were converted to <sc>l-</sc>dopa-carbidopa monotherapy based on the <sc>l-</sc>dopa component of their previous PD therapy. On the last titration day (NJ or PEG-J, whichever was a patient's final titration period), the mean total daily <sc>l-</sc>dopa dose was 1,547.4 mg, which included a mean of 1,537.0 mg from LCIG; only 4.4% (15 of 338) of patients received oral immediate-release <sc>l-</sc>dopa-carbidopa at nighttime, with an average dose of 235 mg. Initial titration during the NJ period was completed in a mean of 4.5 ± 2.2 days. The mean LCIG dose remained relatively constant throughout the study, ranging from 1,551.0 to 1,630.5 mg, depending on time point, and was 1,572.4 mg at last visit (Supporting <xref ref-type="supplementary-material" rid="SD4">Fig. 1</xref>). In the post-PEG-J phase, 76.5% (n = 248) of patients received only <sc>l-</sc>dopa-carbidopa, as LCIG with or without oral <sc>l-</sc>dopa-carbidopa, including 27.8% (n = 90) who received LCIG monotherapy. Among patients receiving adjunctive medications, 12.7% (n = 41) received dopamine agonists, 9.6% (n = 31) amantadine, 3.7% (n = 12) COMT inhibitors, and 1.5% (n = 5) monoamine oxidase (MAO)-B inhibitors (Supporting <xref ref-type="supplementary-material" rid="SD1">Table 1</xref>). At last visit, 27.8% (n = 88) of patients received immediate-release <sc>l-</sc>dopa-carbidopa (mean total dosage: 174.6 mg/night).</p></sec><sec><title>Safety</title><p>AEs were reported in 166 (46.9%) patients during the NJ period; the most common AEs were insomnia (7.9%), complication of device insertion (7.3%), and oropharyngeal pain (6.5%). During the post-PEG-J period, 298 (92.0%) patients experienced AEs (Table <xref ref-type="table" rid="tbl2">2</xref>). The most common were complication of device insertion (34.9%), abdominal pain (31.2%), and procedural pain (20.7%). For the majority of subjects, AEs were mild (18.5%) or moderate (43.8%) and transient, with the highest incidence occurring during week 1 post-PEG-J (Supporting <xref ref-type="supplementary-material" rid="SD5">Fig. 2</xref>), with 65.1% of patients experiencing an AE at week 1 post-PEG-J, compared with 24.4%, 15.4%, and 17.1% by weeks 2, 3, and 4, respectively. SAEs were reported in 105 (32.4%) patients; the most common included complication of device insertion (6.5%), abdominal pain (3.1%), and peritonitis and polyneuropathy (each 2.8%; Table <xref ref-type="table" rid="tbl2">2</xref>). There were no clinically meaningful changes in laboratory values, vital signs, or ECG.</p><fig id="fig02" position="float"><label>Fig. 2</label><caption><p>Mean ± SD daily “off” and “on” times as assessed by a Parkinson's disease diary. *<italic>P</italic> < 0.05; <sup>**</sup><italic>P</italic> < 0.01; <sup>***</sup><italic>P</italic><0.001 versus baseline.</p></caption><graphic xlink:href="mds0030-0500-f2"></graphic></fig><table-wrap id="tbl2" position="float"><label>TABLE 2</label><caption><p>AEs and SAEs in the percutaneous endoscopic gastrojejunostomy treatment period (n = 324)</p></caption><table frame="hsides" rules="groups"><thead><tr><th align="left" rowspan="1" colspan="1">MedDRA Preferred Term<xref ref-type="table-fn" rid="tf2-1">a</xref></th><th align="center" rowspan="1" colspan="1">No. of Patients (%)</th></tr></thead><tbody><tr><td align="left" rowspan="1" colspan="1">Any AE</td><td align="center" rowspan="1" colspan="1">298 (92.0)</td></tr><tr><td align="left" rowspan="1" colspan="1">AEs reported in ≥10%</td><td rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"> Complication of device insertion<xref ref-type="table-fn" rid="tf2-2">b</xref></td><td align="center" rowspan="1" colspan="1">113 (34.9)</td></tr><tr><td align="left" rowspan="1" colspan="1"> Abdominal pain</td><td align="center" rowspan="1" colspan="1">101 (31.2)</td></tr><tr><td align="left" rowspan="1" colspan="1"> Procedural pain</td><td align="center" rowspan="1" colspan="1">67 (20.7)</td></tr><tr><td align="left" rowspan="1" colspan="1"> Nausea</td><td align="center" rowspan="1" colspan="1">54 (16.7)</td></tr><tr><td align="left" rowspan="1" colspan="1"> Excessive granulation tissue</td><td align="center" rowspan="1" colspan="1">52 (16.0)</td></tr><tr><td align="left" rowspan="1" colspan="1"> Postoperative wound infection</td><td align="center" rowspan="1" colspan="1">50 (15.4)</td></tr><tr><td align="left" rowspan="1" colspan="1"> Fall</td><td align="center" rowspan="1" colspan="1">49 (15.1)</td></tr><tr><td align="left" rowspan="1" colspan="1"> Constipation</td><td align="center" rowspan="1" colspan="1">47 (14.5)</td></tr><tr><td align="left" rowspan="1" colspan="1"> Insomnia</td><td align="center" rowspan="1" colspan="1">44 (13.6)</td></tr><tr><td align="left" rowspan="1" colspan="1"> Incision site erythema</td><td align="center" rowspan="1" colspan="1">42 (13.0)</td></tr><tr><td align="left" rowspan="1" colspan="1"> Urinary tract infection</td><td align="center" rowspan="1" colspan="1">37 (11.4)</td></tr><tr><td align="left" rowspan="1" colspan="1">Any SAE</td><td align="center" rowspan="1" colspan="1">105 (32.4)</td></tr><tr><td align="left" rowspan="1" colspan="1">SAEs reported in ≥1%</td><td rowspan="1" colspan="1"></td></tr><tr><td align="left" rowspan="1" colspan="1"> Complication of device insertion<xref ref-type="table-fn" rid="tf2-2">b</xref></td><td align="center" rowspan="1" colspan="1">21 (6.5)</td></tr><tr><td align="left" rowspan="1" colspan="1"> Abdominal pain</td><td align="center" rowspan="1" colspan="1">10 (3.1)</td></tr><tr><td align="left" rowspan="1" colspan="1"> Peritonitis</td><td align="center" rowspan="1" colspan="1">9 (2.8)</td></tr><tr><td align="left" rowspan="1" colspan="1"> Polyneuropathy</td><td align="center" rowspan="1" colspan="1">9 (2.8)</td></tr><tr><td align="left" rowspan="1" colspan="1"> PD<xref ref-type="table-fn" rid="tf2-3">c</xref></td><td align="center" rowspan="1" colspan="1">8 (2.5)</td></tr><tr><td align="left" rowspan="1" colspan="1"> Pneumoperitoneum</td><td align="center" rowspan="1" colspan="1">8 (2.5)</td></tr><tr><td align="left" rowspan="1" colspan="1"> Hip fracture</td><td align="center" rowspan="1" colspan="1">6 (1.9)</td></tr><tr><td align="left" rowspan="1" colspan="1"> Pneumonia</td><td align="center" rowspan="1" colspan="1">6 (1.9)</td></tr><tr><td align="left" rowspan="1" colspan="1"> Device dislocation</td><td align="center" rowspan="1" colspan="1">5 (1.5)</td></tr><tr><td align="left" rowspan="1" colspan="1"> Depression</td><td align="center" rowspan="1" colspan="1">4 (1.2)</td></tr></tbody></table><table-wrap-foot><fn id="tf2-1"><label>a</label><p>A single event could be coded to >1 preferred term.</p></fn><fn id="tf2-2"><label>b</label><p>Events with this term were most often additionally coded to abdominal pain, abdominal discomfort, abdominal distension, flatulence, and pneumoperitoneum.</p></fn><fn id="tf2-3"><label>c</label><p>Patients requiring hospitalization or extended hospitalization resulting from PD.</p></fn></table-wrap-foot></table-wrap><p>Among AEs of special interest, procedure-/device-related AEs were reported for 68.5% of patients, primarily complication of device insertion (33.6%), abdominal pain (26.5%), procedural pain (20.4%), excessive granulation tissue (15.4%), postoperative wound infection (15.1%), incision-site erythema (12.7%), procedural-site reaction (9.3%), postprocedural discharge (7.7%), incision-site pain (6.2%), and pneumoperitoneum (5.9%). There were no treatment-emergent cardiovascular fatalities. Aspiration-related AEs (14.8% of patients) were primarily dyspnea (4.0%), pneumonia (3.1%), gastroesophageal reflux disease (2.2%), pyrexia (2.2%), dysphagia (1.9%), and atelectasis (1.5%). Fourteen aspiration events occurred within 7 days of initial PEG placement and 3 within 7 days of tube replacement/repositioning that required endoscopy. AEs related to polyneuropathy (6.8% of patients) were coded to the following MedDRA preferred terms: polyneuropathy (3.1% [which led to discontinuation for 1 patient]); peripheral sensory neuropathy (0.9%); Guillain-Barré syndrome-like neuropathy (coded as Guillain-Barré Syndrome; see Discussion; 0.6%); mononeuropathy (0.6%); neuralgia (0.6%); neuropathy peripheral (0.6%); and peripheral sensorimotor neuropathy (0.6%). Weight-loss–related AEs occurred in 15.4% of patients.</p><p>Twenty-seven (7.6%) patients had an AE leading to withdrawal, 5 during the NJ period, and 22 patients post-PEG-J. Withdrawals during the NJ period were the result of dysphagia, vomiting, and complication of device insertion in 1 patient as well as pneumonia, QT prolongation, anxiety, and hallucination (1 patient each). In the post-PEG-J period, the most common reasons were complication of device insertion (n = 6), abdominal pain (n = 3), dyskinesia (n = 2), death of unknown etiology (n = 2), and completed suicide (n = 2; both patients had a history of depression). There were 8 subjects who had procedure-/device-related AEs resulting in discontinuation.</p><p>A total of 8 deaths (2.3%) were reported; none were considered treatment related. Seven of these deaths occurred during the LCIG treatment period or within 30 days after PEG-J removal and included deaths attributed to suicide (n = 2), unknown etiology (n = 2), multiple complications (n = 1), cerebrovascular accident (n = 1), and cachexia (n = 1). One patient with a history of deep vein thrombosis (DVT) died 93 days post-PEG-J removal (i.e., not treatment emergent) as a result of DVT.</p><p>Device complications (i.e., related to device function, but not necessarily associated with an AE) were reported for 87.0% of patients: intestinal tube complication (50.9%); pump or stoma complication (35.8% each); and PEG-J or other complication (35.2% each).</p></sec><sec><title>Efficacy</title><p>Off time was significantly decreased from baseline to last visit by 4.4 ± 2.9 hours per day, or 65.6% (<italic>P</italic> < 0.001; <xref ref-type="fig" rid="fig02">Fig. 2</xref> and Supporting <xref ref-type="supplementary-material" rid="SD2">Table 2</xref>). This improvement was sustained throughout all post-PEG-J visits (weeks 4-54; <italic>P</italic> < 0.001). Similarly, on time without troublesome dyskinesia increased by 4.8 ± 3.4 hours per day, or 62.9% (<italic>P</italic> < 0.001), and on time with troublesome dyskinesia decreased by 0.4 ± 2.8 hours per day, or 22.5% (<italic>P</italic> = 0.023). These improvements were sustained at all visits (<italic>P</italic> < 0.05).</p><p>On the CGI-I scale at end of treatment, 22.4% of patients were “very much improved,” 55.5% “much improved,” and 13.7% “minimally improved.” There was no change for 3.1% of patients, whereas 2.8% were “minimally worse,” 1.0% “much worse,” and none were “very much worse.”</p><p>On the efficacy measures commonly associated with function and health-related quality of life (HRQoL), significant improvement (<italic>P</italic> < 0.001) was noted by week 4 of long-term treatment and was maintained through the end of the study (<xref ref-type="fig" rid="fig03">Fig. 3</xref>). From baseline to last visit, the mean change was −4.4 ± 6.5 points for the UPDRS Part II (activities of daily living), +0.064 ±0.203 points for the EQ-5D Summary Index, and +14.0 ± 24.8 points for the EQ-VAS. From screening to last visit, the mean ± SD change in the PDQ-39 Summary Index was −6.9 ± 14.1 points. Seven of the eight PDQ-39 domains (except social support) showed statistically significant mean improvements (Supporting <xref ref-type="supplementary-material" rid="SD3">Table 3</xref>).</p><fig id="fig03" position="float"><label>Fig. 3</label><caption><p>Mean ± SD changes from baseline on other efficacy measures including function and health-related quality of life. <sup>a</sup>Baseline value from screening. <sup>***</sup><italic>P</italic> < 0.001 versus baseline, one-sample <italic>t</italic> test.</p></caption><graphic xlink:href="mds0030-0500-f3"></graphic></fig></sec></sec><sec sec-type="discussion"><title>Discussion</title><p>This prospective study provides long-term safety and efficacy data for over 12 months in the largest cohort to date of patients with advanced PD treated with LCIG. Here, LCIG was initiated as monotherapy, replacing both oral <sc>l-</sc>dopa and other adjunctive PD medications in patients with PD who experienced severe motor complications despite optimized pharmacological therapy. Continuous infusion of LCIG throughout the day led to significant improvements in off time of −4.4 hours per day (65.6%), as assessed by patient-completed diary, which were sustained throughout the 54-week trial. This outcome is of a magnitude expected to be clinically meaningful to patients, well beyond the 1-hour change in off time deemed clinically important in the literature.<xref rid="b28" ref-type="bibr">28</xref> Of note, the reduction in off time corresponded to a significant increase in on time without troublesome dyskinesia. Even with optimized LCIG, there was some residual off time (approximately 2.5 hours in this cohort), but both the physician- and patient-perceived improvements were robust, with significant and enduring improvements in motor function as assessed by the UPDRS and CGI-I, as well as HRQoL as assessed by the PDQ-39 and EuroQoL. In fact, HRQoL improvements began as early as week 4 and were maintained through the duration of the 54-week study period. Furthermore, total daily dosing, after initial titration/optimization, was stable throughout the study, suggesting that patients do not develop tolerance to LCIG. Moreover, although adjunctive therapies were permitted after 28 days, there was low use of these therapies and 76.5% of patients remained on <sc>l-</sc>dopa-carbidopa monotherapy. This is valuable given that it simplifies patient treatment regimens and could decrease AEs resulting from multiple dopaminergic medications.</p><p>The most common AEs in this study were associated with device insertion, were generally transient, and decreased substantially after the first week post-PEG-J tube placement. Device complications were most common in the first week after PEG-J placement. In the NJ phase, insomnia may have been related to causes including hospitalization itself and was deemed not related to the system in the majority of cases. SAEs occurred in 105 (32.4%) patients; the most common included complication of device insertion (6.5%), abdominal pain (3.1%), and peritonitis and polyneuropathy (each 2.8%). There were 2 SAEs of suicide, both in subjects under the age of 65 with a medical history of depression; neither reported suicidal ideation, but patients with PD as a group are at increased risk of suicide (by 5.3-fold in one study),<xref rid="b29" ref-type="bibr">29</xref> and clinically relevant depression has been reported in 35% of patients with PD.<xref rid="b30" ref-type="bibr">30</xref> In a study employing multivariable regression, the only factor associated with suicidal ideation or behavior in advanced PD was severity of depression,<xref rid="b31" ref-type="bibr">31</xref> so physicians should be vigilant about the emotional state of all patients with advanced PD. Considering the patient population in our study (mean 64.1 years old, mean PD duration of 12.5 years; baseline CGI-S of “markedly ill” or worse for approximately two thirds), the procedure was generally well tolerated with few discontinuations resulting from AEs (7.6%). Of the 272 subjects who completed this study, 203 (74.6%) enrolled in the extension study, 66 (24.3%) transitioned to commercial LCIG, and 3 (1.1%) discontinued treatment.</p><p>To further examine procedure-related AEs, an adjudication committee consisting of independent expert gastroenterologists reviewed treatment-emergent AEs and SAEs categorized as “procedure and device-associated events” in the ongoing LCIG phase III program, including this study. The committee found that the rate of gastrointestinal AEs was generally consistent with ranges reported in the literature<xref rid="b32" ref-type="bibr">32</xref>,<xref rid="b33" ref-type="bibr">33</xref> for the PEG-J procedure.<xref rid="b34" ref-type="bibr">34</xref></p><p>Patients with PD are at increased risk of neuropathy. The cause of this is uncertain, but it has been suggested that it may be related to the metabolic effects of long-term <sc>l-</sc>dopa therapy.<xref rid="b35" ref-type="bibr">35</xref> The rate in our study is consistent with reports in the literature for patients with PD receiving <sc>l-</sc>dopa.<xref rid="b36" ref-type="bibr">36</xref> In the LCIG phase III program, an independent committee adjudicated cases associated with polyneuropathy and determined that the cases observed were predominantly subacute or chronic, the severity mild to moderate, the phenotype sensory or sensorimotor, and the neurophysiology was typically consistent with axonal polyneuropathy.<xref rid="b37" ref-type="bibr">37</xref> No patients were deemed to fulfill the criteria for Guillain-Barré syndrome despite 2 AEs being coded as Guillain-Barré syndrome. Although neuropathy screening and monitoring was not standardized at the outset, decreased vitamin B<sub>6</sub>, vitamin B<sub>12</sub>, folic acid, and increased homocysteine and methylmalonic acid appear to have emerged as risk factors for polyneuropathy,<xref rid="b36" ref-type="bibr">36</xref>,<xref rid="b38" ref-type="bibr">38</xref> and measurements at baseline and every 3 months were added by amendment to the LCIG phase III protocols. Future prospective studies examining the incidence of neuropathy would be valuable.</p><p>The open-label design of this trial and lack of a control group are study limitations, in that the potential contributions of placebo effect cannot be assessed. However, the present trial is the largest sample of LCIG-treated patients studied worldwide thus far, which is a key strength. Moreover, these results demonstrate the maintenance of LCIG effects over 12 months, which is consistent with the recently reported 12-week, double-blind, double-dummy, phase III study comparing LCIG with optimized oral immediate-release <sc>l-</sc>dopa-carbidopa (both treatments concomitant with unchanged adjunctive therapies).<xref rid="b15" ref-type="bibr">15</xref> The double-blind study showed that the difference in off time decrease was significant at −1.91 hours (<italic>P</italic> = 0.0015; least squares [LS] mean of −4.04 hours for LCIG [n = 35] vs. −2.14 hours for oral <sc>l-</sc>dopa-carbidopa [n = 31] over an “optimized” baseline). Also in line with our study, the median CGI-I endpoint score was “much improved” for LCIG versus “minimally improved” for oral therapy, the mean UPDRS Part II score changed by −1.8 points (LS mean) in the LCIG arm (3.0-point improvement over oral therapy; <italic>P</italic> = 0.0086), and the PDQ-39 Summary Index score changed by −10.9 points (LS mean) with LCIG (7-point improvement over oral therapy; <italic>P</italic> = 0.0155).</p><p>Safety results in the double-blind study were consistent with our study. The most common AEs were related to the procedure, device, oral <sc>l-</sc>dopa, or underlying disease, most commonly abdominal pain (42%), procedural pain (32%), and nausea (25%). AEs were generally mild to moderate and declined within the first 2 weeks following the PEG-J procedure. Gastrointestinal AEs were typical for a PEG-J procedure.</p><p>Continuous drug delivery is integral to the therapeutic profile of LCIG. In countries where it is approved, LCIG is indicated for the treatment of advanced <sc>l-</sc>dopa-responsive PD with severe motor fluctuations and dyskinesia when available combinations of oral PD medications have not given satisfactory results.<xref rid="b39" ref-type="bibr">39</xref> In this setting, the restricted mean duration of LCIG treatment in Sweden was approximately 7.8 years; 60% of patients were ongoing, and the most common reason for discontinuation was death (unrelated to LCIG).<xref rid="b40" ref-type="bibr">40</xref> Furthermore, when LCIG is initiated, the large majority of patients do not require adjunctive agents and can be maintained on <sc>l-</sc>dopa-carbidopa monotherapy, facilitating dose adjustment for efficacy or managing AEs<xref rid="b14" ref-type="bibr">14</xref> and simplifying patients' therapeutic regimens. Overall, our safety and efficacy results are further reinforced by results from these and other LCIG studies that have been systematically compiled and published.<xref rid="b41" ref-type="bibr">41</xref></p><p>Apomorphine infusion and DBS are also associated with significant reductions in off time and with HRQoL improvements.<xref rid="b13" ref-type="bibr">13</xref>,<xref rid="b42" ref-type="bibr">42</xref>–<xref rid="b50" ref-type="bibr">50</xref> LCIG will provide another treatment option for patients with motor complications despite optimized therapy, offering an additional treatment option suiting patient-specific needs and contraindications.<xref rid="b50" ref-type="bibr">50</xref></p><p>In summary, in this long-term, open-label study, LCIG demonstrated sustained, significant, and clinically meaningful improvements not only in motor complications, but also in HRQoL in advanced PD. LCIG was associated with robust improvements in off and on time, at a consistent mean daily dose throughout the study period, and without worsening dyskinesia throughout 54 weeks. As assessed by the low rate of study withdrawal resulting from AEs (7.6%), LCIG was generally well tolerated. Nonetheless, 92% of the patients reported ≥1 AE, most commonly associated with PEG-J tube placement during the first week post-PEG-J placement. LCIG provides an effective therapeutic option for advanced PD patients with severe motor complications despite optimized oral pharmacologic therapy.</p></sec></body><back><ack><p>AbbVie Inc. funded the study (NCT00335153). AbbVie Inc. participated in the study design, research, analysis, data collection and interpretation, reviewing, and approval of the publication. Funding for editorial, design, and production support was provided by AbbVie Inc. to The Curry Rockefeller Group, LLC; medical writing assistance was provided by Michael Feirtag, Susan Kralian, PhD, Paul V. Shea, Jennifer Kuo, PharmD, and John Norwood of The Curry Rockefeller Group, LLC.</p></ack><sec><title>Study Investigators</title><p>The authors thank the following study investigators for their contributions to this study: Prof. Giovanni Abbruzzese (Universita degli Studi di Genova, Genova, Italy); Alina Agafina, MD, PhD (St. Petersburg City Hospital, St. Petersburg, Russia); Tim Anderson, FRACP, MD (University of Otago, Christchurch, New Zealand); Roongroj Bhidayasiri, MD, FRCP (King Chulalongkom Memorial Hospital, Bangkok, Thailand); Prof. Andrzej Bogucki, MD, PhD (Medical University of Lodz, Lodz, Poland); Prof. Ubaldo Bonuccelli (University of Pisa, Pisa, Italy); James T. Boyd, MD (University of Vermont College of Medicine, Burlington, VT, USA); Dr. Roger Clarnette (Fremantle Hospital, Fremantle, Australia); Dr. Luis Cunha (Hospital da Universidade de Coimbra, Coimbra, Portugal); Dr. Oriol de Fàbregues (Universitat Autonoma de Barcelona, Barcelona, Spain); Prof. Dr. Günther Deuschl (Kiel University, Kiel, Germany); Dirk Dressler, MD, PhD (Hannover Medical School, Hannover, Germany); Andrew Feigin, MD (The Feinstein Institute for Medical Research, Manhasset, NY, USA); Prof. Joaquim J. Ferreira, MD, PhD (Instituto de Medicina Molecular, Lisbon, Portugal); Tanya Gurevich, MD (Tel Aviv Medical Center, Tel Aviv, Israel); Jonathan Harris, MD (Neurologic Consultants, Ft. Lauderdale, FL, USA); Neal Hermanowicz, MD (University of California Irvine, Irvine, CA, USA); Dr. Donald S. Higgins, Jr. (Albany Medical College, Albany, NY, USA); Dr. Andrew Hughes (Austin Health, Melbourne, Australia); Keith L. Hull, Jr., MD (Wake Med Health and Hospitals at Raleigh, Raleigh, NC, USA); Dr. Zygmunt Jamrozik (Samodzielny Publiczny Centralny Szpital, Warsaw, Poland); Thomas E. Kimber, MBBS (Hons), PhD (Royal Adelaide Hospital, Adelaide, Australia); Jaime Kulisevsky, MD, PhD (Sant Pau Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain); Rajeev Kumar, MD (Colorado Neurological Institute, Englewood, CO, USA); Laura Kupila, MD, PhD (Päijät-Häme Central Hospital, Lahti, Finland); Prof. Patricia Limousin (Institute of Neurology, London, UK); Michael A. Lobatz, MD (The Neurology Center and Scripps Health, Encinitas, CA, USA); Dr. Zoltan Mari (John Hopkins Neurology, Baltimore, MD, USA); Juan Carlos Martinez-Castrillo, MD, PhD (Hospital Ramon y Cajal, IRYCIS, Madrid, Spain); Leo Verhagen Metman, MD, PhD (Rush University Medical Center, Chicago, IL, USA); Stuart Mossman, MD, FRACP (Wellington Hospital, Wellington, New Zealand); Prof. Thomas Müller (St. Joseph Hospital Berlin-Weißensee, Berlin, Germany); Prof. Giuseppe Orefice (Azienda Ospedaliera Universitaria, Napoli, Italy); Fernando L. Pagan, MD (Georgetown University Hospital, Washington, DC, USA); Nicolas Phielipp, MD (Toronto Western Hospital, Tornonto, Ontario, Canada); Niphon Poungvarin, MD, FRCP (Siriraj Hospital, Bangkok, Thailand); Dr. Victor Puente (Hospital del Mar, Barcelona, Spain); Brad A. Racette, MD (Washington University School of Medicine, St. Louis, MO, USA); Prof. Ivan Rektor, MD, CSc (Masaryk University, Hospital Sv. Anna, CEITEC, Brno, Czech Republic); Ramon L. Rodriguez, MD (University of Florida, Gainesville, FL, USA); Maria Jose Rosas, MD (Hospital S. João, Porto, Portugal); Evzen Ruzicka, MD, DSc (Vseobecna Fakultnin Nemocnice Praha, Praha, Czech Republic); Joseph M. Savitt, MD, PhD (Parkinson's and Movement Disorders Center of Maryland, Elkridge, MD, USA); Johannes Schwarz, MD (Geriatric Hospital Haag, Haag, Germany); Mustafa S. Siddiqui, MD (Wake Forest University School of Medicine, Winston-Salem, NC, USA); Barry J. Snow, MBChB, FRACP, FRCPC (Auckland City Hospital, Auckland, New Zealand); Martin Sommer, MD (University of Goettingen, Goettingen, Germany); David G. Standaert, MD, PhD (University of Alabama at Birmingham, Birmingham, AL, USA); Fabrizio Stocchi, MD, PhD (IRCCS San Raffaele, Rome, Italy); Oksana Suchowersky, MD, FRCPC (University of Alberta, Edmonton, Alberta, Canada); Paul L. Timmings, MBChB, MD, FRACP (Waikato Hospital, Hamilton, New Zealand); Prof. Eduardo Tolosa (Universitat de Barcelona, Barcelona, Spain); Associate Prof. Martin Vališ, MD, PhD (Charles University, Faculty Hospital, Hradec Kralove, Czech Republic); C.C.P. Verstappen, PhD, MD (Canisius Wilhelmina Hospital, Nijmegen, The Netherlands); Thomas Vogt, MD (University Medical Center, Mainz, Germany); Richard Walsh, MD (Toronto Western Hospital, Toronto, Ontario, Canada); Cheryl Waters, MD (Columbia University, New York, NY, USA); William J. Weiner, MD† (University of Maryland, Baltimore, MD); Christian Winkler, MD, PhD (University Hospital Freiburg, Freiburg, Germany); Jaroslaw Wronka, MD (NZOZ CMHCP Oddzial Neurologiczny, Poznan, Poland); Prof. Eduard Yakupov (LLC Research Medical Complex, Kazan, Russia); Cindy Zadikoff, MD (Northwestern University, Chicago, IL, USA); Mario Zappia, MD (University of Catania, Catania, Italy); Katerina Zarubova, MD (Fakultni Nemocnice Motol, Praha, Czech Republic); and Richard M. Zweig, MD (LSU Health Sciences Center, Shreveport, LA, USA). †29 December 2012.</p></sec><sec><title>Author Roles</title><p>(1) Research Project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript: A. Writing of the First Draft, B. Review and Critique.</p><p>H.H.F.: 1A, 1B, 1C, 2C, 3A, 3B</p><p>D.G.S.: 1A, 1B, 1C, 2C, 3A, 3B</p><p>R.A.H.: 1A, 1B, 1C, 2C, 3A, 3B</p><p>A.E.L.: 1B, 1C, 3B</p><p>V.S.C.F.: 1B, 1C, 3A, 3B</p><p>F.K.: 1B, 1C, 3B</p><p>M.F.L.: 1B, 1C, 3B</p><p>P.O.: 1A, 1B, 2A, 2C, 3A, 3B</p><p>M.S.: 1B, 1C, 3B</p><p>E.Z.Y.: 1B, 1C, 3B</p><p>S.C.: 1B, 1C, 3B</p><p>O.S.: 1B, 1C, 3B</p><p>J.D.: 1B, 1C, 3B</p><p>C.M.H.: 2A, 2B, 3B</p><p>K.C.: 1A, 1B, 1C, 2A, 2C, 3A, 3B</p><p>W.Z.R.: 1A, 1B, 1C, 2A, 2B, 3B</p><p>J.A.B.: 1A, 1B, 1C, 2A, 2C, 3A, 3B</p><p>A.J.E.: 1A, 1B, 1C, 2C, 3A, 3B</p></sec><sec><title>Financial Disclosures</title><p>H.H.F. was a study investigator and has served as a consultant for AbbVie Inc. through a contract between AbbVie Inc. and Cleveland Clinic Foundation; he has not received any personal compensation from AbbVie Inc. D.G.S. was a study investigator and has received compensation from AbbVie Inc. for serving as a consultant and/or participating in scientific advisory boards and from Auspex Inc., Teva Neurosciences, and Serina Therapeutics for serving as a consultant. R.A.H. has received honoraria or payments for consulting, advisory services, or speaking services over the past 12 months from AbbVie Inc., Allergan, AstraZeneca, Biotie Therapeutics, Ceregene, Chelsea Therapeutic, Cleveland Clinic, Eli Lilly, GE Healthcare, Impax Laboratories, Neurocrine, Indus, Ipsen Biopharmaceuticals, Lundbeck, Merck/MSD, Noven Pharmaceuticals, Pfizer, Straken Pharmaceuticals, Targacept, Teva Pharmaceuticals Industries, Ltd., Teva Neuroscience, Upsher-Smith Laboratories, UCB, UCB Pharma SA, University of Houston, US World Meds, Xenoport, and Zambon Company SpA. His institution has received research support over the past 12 months from Abbott Laboratories, Addex Therapeutics, Allergan, AstraZeneca, Biotie Therapeutics, Chelsea Therapeutics, Civitas, GE Healthcare, Impax Laboratories, Ipsen Biopharmaceuticals, Merck/MSD, Merz, the Michael J. Fox Foundation for Parkinson's Research, the National Institute of Neurological Disorder and Stroke, Parkinson Study Group, Schering-Plough, Teva Neuroscience, UCB, and Vita-Pharm. He has received royalties in the last 12 months from the University of South Florida and is supported in part by a Center grant from the National Parkinson Foundation. A.E.L. has served as an advisor for Abbott, AbbVie, Allon Therapeutics, Avanir Pharmaceuticals, Biogen Idec, Boehringer Ingelheim, Ceregene, Lilly, Medtronic, Merck, Novartis, NeuroPhage Pharmaceuticals, Teva, and UCB; received honoraria from Teva, UCB, and AbbVie; received grants from Brain Canada, Canadian Institutes of Health Research, the Edmond J. Safra Philanthropic Foundation, the Michael J. Fox Foundation, the National Parkinson Foundation, Parkinson Society Canada, the Tourette Syndrome Association, and the W. Garfield Weston Foundation; received publishing royalties from Saunders, Wiley-Blackwell, Johns Hopkins Press, and Cambridge University Press; and has served as an expert witness in cases related to the welding industry. V.S.C.F. was a study investigator for, and has also received compensation from, AbbVie Inc. for participating in scientific advisory boards; AbbVie Inc. contributed to funding for a Parkinson disease nurse specialist in the form of a grant to his institution. F.K. was a study investigator for, and has received compensation from, AbbVie Inc. for participating in scientific advisory boards and for serving as a lecturer. M.F.L. has been a study investigator and a speaker for Teva, USWM, Ipsen, and UCB; an advisor/consultant to Teva, USWM, Ipsen, Schering-Plough, Merz, Abbott, Impax, and Baxter; a researcher for the National Institutes of Health ///NIH, Abbott/AbbVie, Schering-Plough, the Parkinson Study Group, USWM, the Michael J. Fox Foundation for Parkinson's Research, Synosia Pharmaceuticals, Merz, and Ipsen; and received foundation grants from the National Parkinson Foundation, the HollyRod Foundation, and the Gene and Kathy Monroe Foundation. P.O. has been a study investigator in AbbVie Inc.– and Britannia-sponsored studies and has received compensation from AbbVie Inc., Britannia, ESP, and Leading Edge for serving as a consultant and lecturer. M.S. was a study investigator in AbbVie Inc.–sponsored studies and has received compensation from AbbVie Inc. for participating in scientific advisory boards. M.S. has also received honoraria for scientific advisory boards and lecture fees from Teva Pharmaceuticals and Britannia Pharmaceuticals. E.Z.Y. was a study investigator and has received compensation from AbbVie Inc. for serving as a lecturer. S.C. was a study investigator and has received compensation from AbbVie Inc. for serving as a consultant, lecturer, and/or participating in scientific advisory boards. O.S. was a study investigator and has received compensation from AbbVie Inc. for serving as a consultant and/or participating in scientific advisory boards. O.S. serves on an advisory board for Allergan and receives honoraria from UpToDate. J.D., C.M.H., K.C., W.Z.R., and J.A.B. are employees of AbbVie Inc. A.J.E. is supported by the K23 career development award (National Institute of Mental Health ///NIMH, 1K23MH092735); has received grant support from CleveMed/Great Lakes NeuroTechnologies and the Michael J. Fox Foundation; has received personal compensation as a consultant/scientific advisory board member for Solvay (now AbbVie), Chelsea Therapeutics, Teva, Impax, Merz, Pfizer, Solstice Neurosciences, Eli Lilly, and US WorldMeds; has received royalties from Lippincott Williams & Wilkins and Cambridge University Press; and has received honoraria from Novartis, UCB, Teva, the American Academy of Neurology, and International Parkinson and Movement Disorder Society. 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Data</title><p>Additional Supporting Information may be found in the online version of this article at the publisher's web-site.</p><supplementary-material content-type="local-data" id="SD1"><caption><p>Supplementary Information Table 1.</p></caption><media mimetype="application" mime-subtype="docx" xlink:href="mds0030-0500-sd1.docx" xlink:type="simple" id="d36e3093" position="anchor"></media></supplementary-material><supplementary-material content-type="local-data" id="SD2"><caption><p>Supplementary Information Table 2.</p></caption><media mimetype="application" mime-subtype="docx" xlink:href="mds0030-0500-sd2.docx" xlink:type="simple" id="d36e3098" position="anchor"></media></supplementary-material><supplementary-material content-type="local-data" id="SD3"><caption><p>Supplementary Information Table 3.</p></caption><media mimetype="application" mime-subtype="docx" xlink:href="mds0030-0500-sd3.docx" xlink:type="simple" id="d36e3103" position="anchor"></media></supplementary-material><supplementary-material content-type="local-data" id="SD4"><caption><p>Supplementary Figure 1. Mean total daily dose of levodopa (LCIG plus immediate-release levodopa). SD, standard deviation; NJ, nasojejunal; PEG-J, percutaneous endoscopic gastrojejunostomy.</p></caption><media mimetype="application" mime-subtype="eps" xlink:href="mds0030-0500-sd4.eps" xlink:type="simple" id="d36e3108" position="anchor"></media></supplementary-material><supplementary-material content-type="local-data" id="SD5"><caption><p>Supplementary Figure 2. Incidence of AEs (≥10% during any time interval) over time. A single event could be coded to >1 preferred term. NJ, nasojejunal; PEG-J, percutaneous endoscopic gastrojejunostomy.</p></caption><media mimetype="application" mime-subtype="eps" xlink:href="mds0030-0500-sd5.eps" xlink:type="simple" id="d36e3113" position="anchor"></media></supplementary-material></sec></back></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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