Bromocriptine Mesylate Attenuates Amyotrophic Lateral Sclerosis: A Phase 2a, Randomized, Double-Blind, Placebo-Controlled Research in Japanese Patients
Identifieur interne : 000423 ( Main/Exploration ); précédent : 000422; suivant : 000424Bromocriptine Mesylate Attenuates Amyotrophic Lateral Sclerosis: A Phase 2a, Randomized, Double-Blind, Placebo-Controlled Research in Japanese Patients
Auteurs : Eiichiro Nagata [Japon] ; Mieko Ogino [Japon] ; Kounosuke Iwamoto [Japon] ; Yasuhisa Kitagawa [Japon] ; Yasuo Iwasaki [Japon] ; Fumihito Yoshii [Japon] ; Joh-E. Ikeda [Japon, Canada]Source :
- PLoS ONE [ 1932-6203 ] ; 2016.
Abstract
Bromocriptine mesylate (BRC), a dopamine D2 receptor agonist has been shown to confer neuroprotection, sustained motor function and slowed disease progression in mouse models of amyotrophic lateral sclerosis (ALS) Here we report a first in human trial in ALS.
A multicenter, Riluzole add-on, randomized, double-blind, placebo controlled 102-week extension BRC clinical trial.
The trial was conducted between January 2009 and March 2012 on 36 Japanese ALS patients. A 12-week treatment with Riluzole observational period was followed by combined treatment (Riluzole + BRC; n = 29 or Riluzole + placebo; n = 7). The dosing commenced at 1.25 mg/day increasing in steps at two weeks intervals to a maximum of 15 mg/day. The efficacy of BRC was evaluated by comparing BRC and placebo groups upon completion of stepwise dosing at 14 weeks 2 points (1st endpoint) and upon completion or discontinuation of the study (2nd endpoint) of the dosing.
Statistics analyses revealed a marginal BRC treatment efficacy with P≦20%to placebo by 1st and 2nd endpoint analysis. In the 1st endpoint analysis, BRC group was significantly effective on the scores of ALSAQ40-communicaton (P = 1.2%), eating and drinking (P = 2.2%), ALSFRS-R total (P = 17.6%), grip strength (P = 19.8%) compared to the placebo group. In the 2nd endpoint analysis, differences between the scores of Limb Norris Scale (P = 18.3%), ALSAQ40-communication (P = 11.9%), eating and drinking (P = 13.6%), and neck forward-bent test (P = 15.4%) of BRC group were detected between the two groups. There was no significant difference between the treatment groups for adverse events or serious drug reactions incidence.
BRC sustains motoneuronal function at least in part through BRC treatment. Further analysis involving a Phase 2b or 3 clinical trial is required but BRC currently shows promise for ALS treatment.
UMIN Clinical Trials
Url:
DOI: 10.1371/journal.pone.0149509
PubMed: 26910108
PubMed Central: 4765990
Affiliations:
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xml:lang="en" level="a" type="main">Bromocriptine Mesylate Attenuates Amyotrophic Lateral Sclerosis: A Phase 2a, Randomized, Double-Blind, Placebo-Controlled Research in Japanese Patients</title><author><name sortKey="Nagata, Eiichiro" sort="Nagata, Eiichiro" uniqKey="Nagata E" first="Eiichiro" last="Nagata">Eiichiro Nagata</name><affiliation wicri:level="1"><nlm:aff id="aff001"><addr-line>Department of Neurology, Tokai University School of Medicine, Isehara, Japan</addr-line></nlm:aff><country xml:lang="fr">Japon</country><wicri:regionArea>Department of Neurology, Tokai University School of Medicine, Isehara</wicri:regionArea><wicri:noRegion>Isehara</wicri:noRegion></affiliation></author><author><name sortKey="Ogino, Mieko" sort="Ogino, Mieko" uniqKey="Ogino M" first="Mieko" last="Ogino">Mieko Ogino</name><affiliation wicri:level="1"><nlm:aff id="aff002"><addr-line>Department of Neurology, Kitasato University School of Medicine, Sagamihara, Japan</addr-line></nlm:aff><country xml:lang="fr">Japon</country><wicri:regionArea>Department of Neurology, Kitasato University School of Medicine, Sagamihara</wicri:regionArea><wicri:noRegion>Sagamihara</wicri:noRegion></affiliation></author><author><name sortKey="Iwamoto, Kounosuke" sort="Iwamoto, Kounosuke" uniqKey="Iwamoto K" first="Kounosuke" last="Iwamoto">Kounosuke Iwamoto</name><affiliation wicri:level="3"><nlm:aff id="aff003"><addr-line>Department of Neurology, Toho University Omori Medical Center, Tokyo, Japan</addr-line></nlm:aff><country xml:lang="fr">Japon</country><wicri:regionArea>Department of Neurology, Toho University Omori Medical Center, Tokyo</wicri:regionArea><placeName><settlement type="city">Tokyo</settlement></placeName></affiliation></author><author><name sortKey="Kitagawa, Yasuhisa" sort="Kitagawa, Yasuhisa" uniqKey="Kitagawa Y" first="Yasuhisa" last="Kitagawa">Yasuhisa Kitagawa</name><affiliation wicri:level="3"><nlm:aff id="aff004"><addr-line>Department of Neurology, Tokai University Hachioji Hospital, Tokyo, Japan</addr-line></nlm:aff><country xml:lang="fr">Japon</country><wicri:regionArea>Department of Neurology, Tokai University Hachioji Hospital, Tokyo</wicri:regionArea><placeName><settlement type="city">Tokyo</settlement></placeName></affiliation></author><author><name sortKey="Iwasaki, Yasuo" sort="Iwasaki, Yasuo" uniqKey="Iwasaki Y" first="Yasuo" last="Iwasaki">Yasuo Iwasaki</name><affiliation wicri:level="3"><nlm:aff id="aff003"><addr-line>Department of Neurology, Toho University Omori Medical Center, Tokyo, Japan</addr-line></nlm:aff><country xml:lang="fr">Japon</country><wicri:regionArea>Department of Neurology, Toho University Omori Medical Center, Tokyo</wicri:regionArea><placeName><settlement type="city">Tokyo</settlement></placeName></affiliation></author><author><name sortKey="Yoshii, Fumihito" sort="Yoshii, Fumihito" uniqKey="Yoshii F" first="Fumihito" last="Yoshii">Fumihito Yoshii</name><affiliation wicri:level="1"><nlm:aff id="aff005"><addr-line>Department of Neurology, Tokai University Oiso Hospital, Kanagawa, Japan</addr-line></nlm:aff><country xml:lang="fr">Japon</country><wicri:regionArea>Department of Neurology, Tokai University Oiso Hospital, Kanagawa</wicri:regionArea><wicri:noRegion>Kanagawa</wicri:noRegion></affiliation></author><author><name sortKey="Ikeda, Joh E" sort="Ikeda, Joh E" uniqKey="Ikeda J" first="Joh-E." last="Ikeda">Joh-E. Ikeda</name><affiliation wicri:level="1"><nlm:aff id="aff006"><addr-line>Molecular Neurology, Faculty of Medicine, Kitasato University School of Medicine, Sagamihara, Japan</addr-line></nlm:aff><country xml:lang="fr">Japon</country><wicri:regionArea>Molecular Neurology, Faculty of Medicine, Kitasato University School of Medicine, Sagamihara</wicri:regionArea><wicri:noRegion>Sagamihara</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:aff id="aff007"><addr-line>Department of Pediatrics, Faculty of Medicine, University of Ottawa, ARC/Children’s Hospital of Eastern Ontario, Ottawa, Canada</addr-line></nlm:aff><country xml:lang="fr">Canada</country><wicri:regionArea>Department of Pediatrics, Faculty of Medicine, University of Ottawa, ARC/Children’s Hospital of Eastern Ontario, Ottawa</wicri:regionArea><wicri:noRegion>Ottawa</wicri:noRegion></affiliation></author></analytic><series><title level="j">PLoS ONE</title><idno type="eISSN">1932-6203</idno><imprint><date when="2016">2016</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><sec id="sec001"><title>Objective</title><p>Bromocriptine mesylate (BRC), a dopamine D2 receptor agonist has been shown to confer neuroprotection, sustained motor function and slowed disease progression in mouse models of amyotrophic lateral sclerosis (ALS) Here we report a first in human trial in ALS.</p></sec><sec id="sec002"><title>Design</title><p>A multicenter, Riluzole add-on, randomized, double-blind, placebo controlled 102-week extension BRC clinical trial.</p></sec><sec id="sec003"><title>Methods</title><p>The trial was conducted between January 2009 and March 2012 on 36 Japanese ALS patients. A 12-week treatment with Riluzole observational period was followed by combined treatment (Riluzole + BRC; n = 29 or Riluzole + placebo; n = 7). The dosing commenced at 1.25 mg/day increasing in steps at two weeks intervals to a maximum of 15 mg/day. The efficacy of BRC was evaluated by comparing BRC and placebo groups upon completion of stepwise dosing at 14 weeks 2 points (1<sup>st</sup> endpoint) and upon completion or discontinuation of the study (2<sup>nd</sup> endpoint) of the dosing.</p></sec><sec id="sec004"><title>Results</title><p>Statistics analyses revealed a marginal BRC treatment efficacy with P≦20%to placebo by 1<sup>st</sup> and 2<sup>nd</sup> endpoint analysis. In the 1<sup>st</sup> endpoint analysis, BRC group was significantly effective on the scores of ALSAQ40-communicaton (P = 1.2%), eating and drinking (P = 2.2%), ALSFRS-R total (P = 17.6%), grip strength (P = 19.8%) compared to the placebo group. In the 2<sup>nd</sup> endpoint analysis, differences between the scores of Limb Norris Scale (P = 18.3%), ALSAQ40-communication (P = 11.9%), eating and drinking (P = 13.6%), and neck forward-bent test (P = 15.4%) of BRC group were detected between the two groups. There was no significant difference between the treatment groups for adverse events or serious drug reactions incidence.</p></sec><sec id="sec005"><title>Conclusions</title><p>BRC sustains motoneuronal function at least in part through BRC treatment. Further analysis involving a Phase 2b or 3 clinical trial is required but BRC currently shows promise for ALS treatment.</p></sec><sec id="sec006"><title>Trial Registration</title><p>UMIN Clinical Trials <ext-link ext-link-type="uri" xlink:href="https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr.cgi?function=brows&action=brows&type=summary&recptno=R000005640&language=E">UMIN000008527</ext-link></p></sec></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Rowland, Lp" uniqKey="Rowland L">LP Rowland</name></author><author><name sortKey="Shneider, Na" uniqKey="Shneider N">NA Shneider</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Sreedharan, J" uniqKey="Sreedharan J">J Sreedharan</name></author><author><name sortKey="Brown, Rh" uniqKey="Brown R">RH Brown</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Barber, Sc" uniqKey="Barber S">SC Barber</name></author><author><name 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sortKey="Kondo, M" uniqKey="Kondo M">M Kondo</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Tanaka, K" uniqKey="Tanaka K">K Tanaka</name></author><author><name sortKey="Kanno, T" uniqKey="Kanno T">T Kanno</name></author><author><name sortKey="Yanagisawa, Y" uniqKey="Yanagisawa Y">Y Yanagisawa</name></author><author><name sortKey="Yasutake, K" uniqKey="Yasutake K">K Yasutake</name></author><author><name sortKey="Hadano, S" uniqKey="Hadano S">S Hadano</name></author><author><name sortKey="Yoshii, F" uniqKey="Yoshii F">F Yoshii</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Liu, Gt" uniqKey="Liu G">GT Liu</name></author><author><name sortKey="Hwang, Cs" uniqKey="Hwang C">CS Hwang</name></author><author><name sortKey="Hsieh, Ch" uniqKey="Hsieh C">CH Hsieh</name></author><author><name sortKey="Lu, Ch" uniqKey="Lu C">CH Lu</name></author><author><name sortKey="Chang, Sly" uniqKey="Chang S">SLY Chang</name></author><author><name sortKey="Huang, Cf" uniqKey="Huang C">CF Huang</name></author></analytic></biblStruct></listBibl></div1></back></TEI><affiliations><list><country><li>Canada</li><li>Japon</li></country><settlement><li>Tokyo</li></settlement></list><tree><country name="Japon"><noRegion><name sortKey="Nagata, Eiichiro" sort="Nagata, Eiichiro" uniqKey="Nagata E" first="Eiichiro" last="Nagata">Eiichiro Nagata</name></noRegion><name sortKey="Ikeda, Joh E" sort="Ikeda, Joh E" uniqKey="Ikeda J" first="Joh-E." last="Ikeda">Joh-E. Ikeda</name><name sortKey="Iwamoto, Kounosuke" sort="Iwamoto, Kounosuke" uniqKey="Iwamoto K" first="Kounosuke" last="Iwamoto">Kounosuke Iwamoto</name><name sortKey="Iwasaki, Yasuo" sort="Iwasaki, Yasuo" uniqKey="Iwasaki Y" first="Yasuo" last="Iwasaki">Yasuo Iwasaki</name><name sortKey="Kitagawa, Yasuhisa" sort="Kitagawa, Yasuhisa" uniqKey="Kitagawa Y" first="Yasuhisa" last="Kitagawa">Yasuhisa Kitagawa</name><name sortKey="Ogino, Mieko" sort="Ogino, Mieko" uniqKey="Ogino M" first="Mieko" last="Ogino">Mieko Ogino</name><name sortKey="Yoshii, Fumihito" sort="Yoshii, Fumihito" uniqKey="Yoshii F" first="Fumihito" last="Yoshii">Fumihito Yoshii</name></country><country name="Canada"><noRegion><name sortKey="Ikeda, Joh E" sort="Ikeda, Joh E" uniqKey="Ikeda J" first="Joh-E." last="Ikeda">Joh-E. Ikeda</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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