Challenges assessing clinical endpoints in early Huntington disease
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Auteurs : Jane S. Paulsen [États-Unis] ; Chiachi Wang [États-Unis] ; Kevin Duff [États-Unis] ; Roger Barker [Royaume-Uni] ; Martha Nance [États-Unis] ; Leigh Beglinger [États-Unis] ; David Moser [États-Unis] ; Janet K. Williams [États-Unis] ; Sheila Simpson [Royaume-Uni] ; Douglas Langbehn [États-Unis] ; Daniel P. Van Kammen [États-Unis]Source :
- Movement disorders : official journal of the Movement Disorder Society [ 0885-3185 ] ; 2010.
English descriptors
- KwdEn :
- MESH :
- diagnosis : Huntington Disease.
- genetics : Huntington Disease.
- methods : Endpoint Determination.
- therapy : Huntington Disease.
- Adolescent, Adult, Aged, Clinical Trials as Topic, Female, Genetic Testing, Humans, Longitudinal Studies, Male, Middle Aged.
Abstract
The primary aim of this study was to evaluate the current accepted standard clinical endpoint for the earliest-studied HD participants likely to be recruited into clinical trials. Since the advent of genetic testing for HD, it is possible to identify gene carriers prior to the diagnosis of disease, which opens up the possibility of clinical trials of disease-modifying treatments in clinically asymptomatic persons. Current accepted standard clinical endpoints were examined as part of a multi-national, 32-site, longitudinal, observational study of 786 research participants currently in the HD prodrome (gene-positive but not clinically diagnosed). Clinical signs and symptoms were used to prospectively predict functional loss as assessed by current accepted standard endpoints over 8 years of follow up. Functional capacity measures were not sensitive for HD in the prodrome; over 88% scored at ceiling. Prospective evaluation revealed that the first functional loss was in their accustomed work. In a survival analysis, motor, cognitive, and psychiatric measures were all predictors of job change. To our knowledge, this is the first prospective study ever conducted on the emergence of functional loss secondary to brain disease. We conclude that future clinical trials designed for very early disease will require the development of new and more sensitive measures of real-life function.
Url:
DOI: 10.1002/mds.23337
PubMed: 20623772
PubMed Central: 2978744
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Paulsen</name><affiliation wicri:level="2"><nlm:aff id="A1">Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City, IA, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City, IA</wicri:regionArea><placeName><region type="state">Iowa</region></placeName></affiliation><affiliation wicri:level="2"><nlm:aff id="A2">Department of Neurology, University of Iowa Carver College of Medicine, Iowa City, IA, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Neurology, University of Iowa Carver College of Medicine, Iowa City, IA</wicri:regionArea><placeName><region type="state">Iowa</region></placeName></affiliation></author><author><name sortKey="Wang, Chiachi" sort="Wang, Chiachi" uniqKey="Wang C" first="Chiachi" last="Wang">Chiachi Wang</name><affiliation wicri:level="2"><nlm:aff id="A1">Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City, IA, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City, IA</wicri:regionArea><placeName><region type="state">Iowa</region></placeName></affiliation></author><author><name sortKey="Duff, Kevin" sort="Duff, Kevin" uniqKey="Duff K" first="Kevin" last="Duff">Kevin Duff</name><affiliation wicri:level="2"><nlm:aff id="A1">Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City, IA, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City, IA</wicri:regionArea><placeName><region type="state">Iowa</region></placeName></affiliation></author><author><name sortKey="Barker, Roger" sort="Barker, Roger" uniqKey="Barker R" first="Roger" last="Barker">Roger Barker</name><affiliation wicri:level="1"><nlm:aff id="A3">Cambridge Center for Brain Repair, Cambridge, UK</nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Cambridge Center for Brain Repair, Cambridge</wicri:regionArea><wicri:noRegion>Cambridge</wicri:noRegion></affiliation></author><author><name sortKey="Nance, Martha" sort="Nance, Martha" uniqKey="Nance M" first="Martha" last="Nance">Martha Nance</name><affiliation wicri:level="2"><nlm:aff id="A4">Department of Neurology, Park Nicollet Clinic, St. Louis Park, MN, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Neurology, Park Nicollet Clinic, St. Louis Park, MN</wicri:regionArea><placeName><region type="state">Minnesota</region></placeName></affiliation></author><author><name sortKey="Beglinger, Leigh" sort="Beglinger, Leigh" uniqKey="Beglinger L" first="Leigh" last="Beglinger">Leigh Beglinger</name><affiliation wicri:level="2"><nlm:aff id="A1">Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City, IA, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City, IA</wicri:regionArea><placeName><region type="state">Iowa</region></placeName></affiliation></author><author><name sortKey="Moser, David" sort="Moser, David" uniqKey="Moser D" first="David" last="Moser">David Moser</name><affiliation wicri:level="2"><nlm:aff id="A1">Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City, IA, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City, IA</wicri:regionArea><placeName><region type="state">Iowa</region></placeName></affiliation></author><author><name sortKey="Williams, Janet K" sort="Williams, Janet K" uniqKey="Williams J" first="Janet K." last="Williams">Janet K. 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Van Kammen</name><affiliation wicri:level="2"><nlm:aff id="A8">Advisor to the CHDI Foundation, CHDI Management, Inc., Princeton, NJ, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Advisor to the CHDI Foundation, CHDI Management, Inc., Princeton, NJ</wicri:regionArea><placeName><region type="state">New Jersey</region></placeName></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">20623772</idno><idno type="pmc">2978744</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2978744</idno><idno type="RBID">PMC:2978744</idno><idno type="doi">10.1002/mds.23337</idno><date when="2010">2010</date><idno type="wicri:Area/Pmc/Corpus">000098</idno><idno type="wicri:Area/Pmc/Curation">000098</idno><idno type="wicri:Area/Pmc/Checkpoint">000360</idno><idno type="wicri:source">PubMed</idno><idno type="wicri:Area/PubMed/Corpus">001765</idno><idno type="wicri:Area/PubMed/Curation">001765</idno><idno type="wicri:Area/PubMed/Checkpoint">001997</idno><idno type="wicri:Area/Ncbi/Merge">002C52</idno><idno type="wicri:Area/Ncbi/Curation">002C52</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Challenges assessing clinical endpoints in early Huntington disease</title><author><name sortKey="Paulsen, Jane S" sort="Paulsen, Jane S" uniqKey="Paulsen J" first="Jane S." last="Paulsen">Jane S. Paulsen</name><affiliation wicri:level="2"><nlm:aff id="A1">Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City, IA, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City, IA</wicri:regionArea><placeName><region type="state">Iowa</region></placeName></affiliation><affiliation wicri:level="2"><nlm:aff id="A2">Department of Neurology, University of Iowa Carver College of Medicine, Iowa City, IA, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Neurology, University of Iowa Carver College of Medicine, Iowa City, IA</wicri:regionArea><placeName><region type="state">Iowa</region></placeName></affiliation></author><author><name sortKey="Wang, Chiachi" sort="Wang, Chiachi" uniqKey="Wang C" first="Chiachi" last="Wang">Chiachi Wang</name><affiliation wicri:level="2"><nlm:aff id="A1">Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City, IA, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City, IA</wicri:regionArea><placeName><region type="state">Iowa</region></placeName></affiliation></author><author><name sortKey="Duff, Kevin" sort="Duff, Kevin" uniqKey="Duff K" first="Kevin" last="Duff">Kevin Duff</name><affiliation wicri:level="2"><nlm:aff id="A1">Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City, IA, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City, IA</wicri:regionArea><placeName><region type="state">Iowa</region></placeName></affiliation></author><author><name sortKey="Barker, Roger" sort="Barker, Roger" uniqKey="Barker R" first="Roger" last="Barker">Roger Barker</name><affiliation wicri:level="1"><nlm:aff id="A3">Cambridge Center for Brain Repair, Cambridge, UK</nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Cambridge Center for Brain Repair, Cambridge</wicri:regionArea><wicri:noRegion>Cambridge</wicri:noRegion></affiliation></author><author><name sortKey="Nance, Martha" sort="Nance, Martha" uniqKey="Nance M" first="Martha" last="Nance">Martha Nance</name><affiliation wicri:level="2"><nlm:aff id="A4">Department of Neurology, Park Nicollet Clinic, St. Louis Park, MN, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Neurology, Park Nicollet Clinic, St. Louis Park, MN</wicri:regionArea><placeName><region type="state">Minnesota</region></placeName></affiliation></author><author><name sortKey="Beglinger, Leigh" sort="Beglinger, Leigh" uniqKey="Beglinger L" first="Leigh" last="Beglinger">Leigh Beglinger</name><affiliation wicri:level="2"><nlm:aff id="A1">Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City, IA, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City, IA</wicri:regionArea><placeName><region type="state">Iowa</region></placeName></affiliation></author><author><name sortKey="Moser, David" sort="Moser, David" uniqKey="Moser D" first="David" last="Moser">David Moser</name><affiliation wicri:level="2"><nlm:aff id="A1">Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City, IA, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City, IA</wicri:regionArea><placeName><region type="state">Iowa</region></placeName></affiliation></author><author><name sortKey="Williams, Janet K" sort="Williams, Janet K" uniqKey="Williams J" first="Janet K." last="Williams">Janet K. Williams</name><affiliation wicri:level="4"><nlm:aff id="A5">College of Nursing, University of Iowa, Iowa City, IA, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>College of Nursing, University of Iowa, Iowa City, IA</wicri:regionArea><placeName><region type="state">Iowa</region><settlement type="city">Iowa City</settlement></placeName><orgName type="university">Université de l'Iowa</orgName></affiliation></author><author><name sortKey="Simpson, Sheila" sort="Simpson, Sheila" uniqKey="Simpson S" first="Sheila" last="Simpson">Sheila Simpson</name><affiliation wicri:level="2"><nlm:aff id="A6">North of Scotland Clinical Genetics Service, Aberdeen, Scotland</nlm:aff><country>Royaume-Uni</country><placeName><region type="country">Écosse</region></placeName><wicri:cityArea>North of Scotland Clinical Genetics Service, Aberdeen</wicri:cityArea></affiliation></author><author><name sortKey="Langbehn, Douglas" sort="Langbehn, Douglas" uniqKey="Langbehn D" first="Douglas" last="Langbehn">Douglas Langbehn</name><affiliation wicri:level="2"><nlm:aff id="A1">Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City, IA, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City, IA</wicri:regionArea><placeName><region type="state">Iowa</region></placeName></affiliation><affiliation wicri:level="2"><nlm:aff id="A7">Department of Biostatistics, University of Iowa College of Public Health, Iowa City, IA, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Biostatistics, University of Iowa College of Public Health, Iowa City, IA</wicri:regionArea><placeName><region type="state">Iowa</region></placeName></affiliation></author><author><name sortKey="Van Kammen, Daniel P" sort="Van Kammen, Daniel P" uniqKey="Van Kammen D" first="Daniel P." last="Van Kammen">Daniel P. Van Kammen</name><affiliation wicri:level="2"><nlm:aff id="A8">Advisor to the CHDI Foundation, CHDI Management, Inc., Princeton, NJ, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Advisor to the CHDI Foundation, CHDI Management, Inc., Princeton, NJ</wicri:regionArea><placeName><region type="state">New Jersey</region></placeName></affiliation></author></analytic><series><title level="j">Movement disorders : official journal of the Movement Disorder Society</title><idno type="ISSN">0885-3185</idno><idno type="eISSN">1531-8257</idno><imprint><date when="2010">2010</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Adolescent</term><term>Adult</term><term>Aged</term><term>Clinical Trials as Topic</term><term>Endpoint Determination (methods)</term><term>Female</term><term>Genetic Testing</term><term>Humans</term><term>Huntington Disease (diagnosis)</term><term>Huntington Disease (genetics)</term><term>Huntington Disease (therapy)</term><term>Longitudinal Studies</term><term>Male</term><term>Middle Aged</term></keywords><keywords scheme="MESH" qualifier="diagnosis" xml:lang="en"><term>Huntington Disease</term></keywords><keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Huntington Disease</term></keywords><keywords scheme="MESH" qualifier="methods" xml:lang="en"><term>Endpoint Determination</term></keywords><keywords scheme="MESH" qualifier="therapy" xml:lang="en"><term>Huntington Disease</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Adolescent</term><term>Adult</term><term>Aged</term><term>Clinical Trials as Topic</term><term>Female</term><term>Genetic Testing</term><term>Humans</term><term>Longitudinal Studies</term><term>Male</term><term>Middle Aged</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p id="P1">The primary aim of this study was to evaluate the current accepted standard clinical endpoint for the earliest-studied HD participants likely to be recruited into clinical trials. Since the advent of genetic testing for HD, it is possible to identify gene carriers prior to the diagnosis of disease, which opens up the possibility of clinical trials of disease-modifying treatments in clinically asymptomatic persons. Current accepted standard clinical endpoints were examined as part of a multi-national, 32-site, longitudinal, observational study of 786 research participants currently in the HD prodrome (gene-positive but not clinically diagnosed). Clinical signs and symptoms were used to prospectively predict functional loss as assessed by current accepted standard endpoints over 8 years of follow up. Functional capacity measures were not sensitive for HD in the prodrome; over 88% scored at ceiling. Prospective evaluation revealed that the first functional loss was in their accustomed work. In a survival analysis, motor, cognitive, and psychiatric measures were all predictors of job change. To our knowledge, this is the first prospective study ever conducted on the emergence of functional loss secondary to brain disease. We conclude that future clinical trials designed for very early disease will require the development of new and more sensitive measures of real-life function.</p></div></front></TEI></record>Pour manipuler ce document sous Unix (Dilib)
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