A proof‐of‐concept, randomized, placebo‐controlled, multiple cross‐overs (n‐of‐1) study of naftazone in Parkinson’s disease
Identifieur interne : 000141 ( France/Analysis ); précédent : 000140; suivant : 000142A proof‐of‐concept, randomized, placebo‐controlled, multiple cross‐overs (n‐of‐1) study of naftazone in Parkinson’s disease
Auteurs : Olivier Rascol [France] ; Joaquim Ferreira [Portugal] ; Laurence Nègre-Pages [France] ; Santiago Perez-Lloret [France] ; Lucette Lacomblez [France] ; Monique Galitzky [France] ; Jean-Christophe Lemarié [France] ; Jean-Christophe Corvol [France] ; Jonathan M. Brotchie [Canada] ; Laura Bossi [France]Source :
- Fundamental & Clinical Pharmacology [ 0767-3981 ] ; 2012-08.
Descripteurs français
- Pascal (Inist)
English descriptors
- KwdEn :
Abstract
To explore for the first time the tolerability and efficacy of naftazone in patients with Parkinson’s disease (PD). Proof‐of‐concept, randomized, double‐blind, placebo‐controlled, multiple‐cross‐over n‐of‐1 study in patients with PD with wearing‐off and dyskinesias. Naftazone was titrated up to 120 mg/day during an initial single‐blind dose‐finding phase. Seven patients entered the placebo‐controlled phase (four consecutive 28‐day cross‐overs). Three outcome measures were used to collect preliminary indices of efficacy: (i) 48‐h ON‐OFF diaries; (ii) Unified PD Rating Scale (UPDRS) part III while ON; (iii) seven‐point Likert scale to assess “patients’ discomfort caused by dyskinesias” (Q1) and ‘disability during OFF‐periods’ (Q2). A ‘responder’ analysis (proportion of patients with mean treatment effect [naftazone minus placebo] favoring naftazone over the 4 cross‐over periods) was used. Treatment effects were derived from mixed‐effects anova. On diaries, 5/7 patients responded to naftazone for ‘ON‐time with troublesome dyskinesia’ (reduced time, treatment effect: −49 [95% CI: −93/−4] min, P = 0.03), 6/7 regarding ‘ON‐time without troublesome dyskinesia’ (increased time, treatment effect: 35 [−19/88], P = 0.2). No trend was observed for ‘OFF’ time. There were 7/7 ‘responders’ regarding UPDRSIII (reduced score, treatment effect: −2.1[−4.5/0.2], P = 0.08). The 7‐point scales did not show clear trends in favor of naftazone (3/7 responders for Q1 and 4/7 for Q2). Four of the seven patients reported adverse events after randomization, mostly related to the CNS (mild: 2, severe: 2). These pilot findings are consistent with preclinical data in primates and support the hypothesis that naftazone may have antiparkinsonian and antidyskinetic effects in humans that deserve further clinical investigation.
Url:
DOI: 10.1111/j.1472-8206.2011.00951.x
Affiliations:
- Canada, France, Portugal
- Midi-Pyrénées, Occitanie (région administrative), Île-de-France
- Paris, Toulouse
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ISTEX:4CECFC3291A09995B8913637D0B2BDB70DE0BD07Le document en format XML
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nuts="2">Île-de-France</region></placeName></affiliation><affiliation wicri:level="1"><country xml:lang="fr">France</country><wicri:regionArea>INSERM, CIC 9503, Paris F‐75013</wicri:regionArea><placeName><settlement type="city">Paris</settlement><region type="région" nuts="2">Île-de-France</region></placeName></affiliation></author><author><name sortKey="Brotchie, Jonathan M" sort="Brotchie, Jonathan M" uniqKey="Brotchie J" first="Jonathan M." last="Brotchie">Jonathan M. Brotchie</name><affiliation wicri:level="1"><country xml:lang="fr">Canada</country><wicri:regionArea>Toronto Western Research Institute, University Health Network, Toronto, ON</wicri:regionArea><wicri:noRegion>ON</wicri:noRegion></affiliation></author><author><name sortKey="Bossi, Laura" sort="Bossi, Laura" uniqKey="Bossi L" first="Laura" last="Bossi">Laura Bossi</name><affiliation wicri:level="1"><country xml:lang="fr">France</country><wicri:regionArea>Faust Pharmaceutical, Illkirch Graffenstaden</wicri:regionArea><wicri:noRegion>Illkirch Graffenstaden</wicri:noRegion><wicri:noRegion>Illkirch Graffenstaden</wicri:noRegion></affiliation></author></analytic><monogr></monogr><series><title level="j">Fundamental & Clinical Pharmacology</title><idno type="ISSN">0767-3981</idno><idno type="eISSN">1472-8206</idno><imprint><publisher>Blackwell Publishing Ltd</publisher><pubPlace>Oxford, UK</pubPlace><date type="published" when="2012-08">2012-08</date><biblScope unit="volume">26</biblScope><biblScope unit="issue">4</biblScope><biblScope unit="page" from="557">557</biblScope><biblScope unit="page" to="564">564</biblScope></imprint><idno type="ISSN">0767-3981</idno></series><idno type="istex">4CECFC3291A09995B8913637D0B2BDB70DE0BD07</idno><idno type="DOI">10.1111/j.1472-8206.2011.00951.x</idno><idno type="ArticleID">FCP951</idno></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0767-3981</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Clinical trial</term><term>Dyskinesia</term><term>Glutamate</term><term>Hemostatic</term><term>Motor control</term><term>Naftazone</term><term>Parkinson disease</term><term>Parkinson’s disease</term><term>Placebo</term><term>Randomization</term><term>dyskinesia</term><term>glutamate</term><term>naftazone</term><term>n‐of‐1 trial</term></keywords><keywords scheme="Pascal" xml:lang="fr"><term>Contrôle moteur</term><term>Dyskinésie</term><term>Essai clinique</term><term>Glutamate</term><term>Hémostatique</term><term>Maladie de Parkinson</term><term>Naftazone</term><term>Placebo</term><term>Randomisation</term></keywords></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">To explore for the first time the tolerability and efficacy of naftazone in patients with Parkinson’s disease (PD). Proof‐of‐concept, randomized, double‐blind, placebo‐controlled, multiple‐cross‐over n‐of‐1 study in patients with PD with wearing‐off and dyskinesias. Naftazone was titrated up to 120 mg/day during an initial single‐blind dose‐finding phase. Seven patients entered the placebo‐controlled phase (four consecutive 28‐day cross‐overs). Three outcome measures were used to collect preliminary indices of efficacy: (i) 48‐h ON‐OFF diaries; (ii) Unified PD Rating Scale (UPDRS) part III while ON; (iii) seven‐point Likert scale to assess “patients’ discomfort caused by dyskinesias” (Q1) and ‘disability during OFF‐periods’ (Q2). A ‘responder’ analysis (proportion of patients with mean treatment effect [naftazone minus placebo] favoring naftazone over the 4 cross‐over periods) was used. Treatment effects were derived from mixed‐effects anova. On diaries, 5/7 patients responded to naftazone for ‘ON‐time with troublesome dyskinesia’ (reduced time, treatment effect: −49 [95% CI: −93/−4] min, P = 0.03), 6/7 regarding ‘ON‐time without troublesome dyskinesia’ (increased time, treatment effect: 35 [−19/88], P = 0.2). No trend was observed for ‘OFF’ time. There were 7/7 ‘responders’ regarding UPDRSIII (reduced score, treatment effect: −2.1[−4.5/0.2], P = 0.08). The 7‐point scales did not show clear trends in favor of naftazone (3/7 responders for Q1 and 4/7 for Q2). Four of the seven patients reported adverse events after randomization, mostly related to the CNS (mild: 2, severe: 2). These pilot findings are consistent with preclinical data in primates and support the hypothesis that naftazone may have antiparkinsonian and antidyskinetic effects in humans that deserve further clinical investigation.</div></front></TEI><affiliations><list><country><li>Canada</li><li>France</li><li>Portugal</li></country><region><li>Midi-Pyrénées</li><li>Occitanie (région administrative)</li><li>Île-de-France</li></region><settlement><li>Paris</li><li>Toulouse</li></settlement></list><tree><country name="France"><noRegion><name sortKey="Rascol, Olivier" sort="Rascol, Olivier" uniqKey="Rascol O" first="Olivier" last="Rascol">Olivier Rascol</name></noRegion><name sortKey="Bossi, Laura" sort="Bossi, Laura" uniqKey="Bossi L" first="Laura" last="Bossi">Laura Bossi</name><name sortKey="Corvol, Jean Hristophe" sort="Corvol, Jean Hristophe" uniqKey="Corvol J" first="Jean-Christophe" last="Corvol">Jean-Christophe Corvol</name><name sortKey="Corvol, Jean Hristophe" sort="Corvol, Jean Hristophe" uniqKey="Corvol J" first="Jean-Christophe" last="Corvol">Jean-Christophe Corvol</name><name sortKey="Corvol, Jean Hristophe" sort="Corvol, Jean Hristophe" uniqKey="Corvol J" first="Jean-Christophe" last="Corvol">Jean-Christophe Corvol</name><name sortKey="Galitzky, Monique" sort="Galitzky, Monique" uniqKey="Galitzky M" first="Monique" last="Galitzky">Monique Galitzky</name><name sortKey="Galitzky, Monique" sort="Galitzky, Monique" uniqKey="Galitzky M" first="Monique" last="Galitzky">Monique Galitzky</name><name sortKey="Lacomblez, Lucette" sort="Lacomblez, Lucette" uniqKey="Lacomblez L" first="Lucette" last="Lacomblez">Lucette Lacomblez</name><name sortKey="Lemarie, Jean Hristophe" sort="Lemarie, Jean Hristophe" uniqKey="Lemarie J" first="Jean-Christophe" last="Lemarié">Jean-Christophe Lemarié</name><name sortKey="Negre Ages, Laurence" sort="Negre Ages, Laurence" uniqKey="Negre Ages L" first="Laurence" last="Nègre-Pages">Laurence Nègre-Pages</name><name sortKey="Negre Ages, Laurence" sort="Negre Ages, Laurence" uniqKey="Negre Ages L" first="Laurence" last="Nègre-Pages">Laurence Nègre-Pages</name><name sortKey="Negre Ages, Laurence" sort="Negre Ages, Laurence" uniqKey="Negre Ages L" first="Laurence" last="Nègre-Pages">Laurence Nègre-Pages</name><name sortKey="Perez Loret, Santiago" sort="Perez Loret, Santiago" uniqKey="Perez Loret S" first="Santiago" last="Perez-Lloret">Santiago Perez-Lloret</name><name sortKey="Perez Loret, Santiago" sort="Perez Loret, Santiago" uniqKey="Perez Loret S" first="Santiago" last="Perez-Lloret">Santiago Perez-Lloret</name><name sortKey="Rascol, Olivier" sort="Rascol, Olivier" uniqKey="Rascol O" first="Olivier" last="Rascol">Olivier Rascol</name><name sortKey="Rascol, Olivier" sort="Rascol, Olivier" uniqKey="Rascol O" first="Olivier" last="Rascol">Olivier Rascol</name></country><country name="Portugal"><noRegion><name sortKey="Ferreira, Joaquim" sort="Ferreira, Joaquim" uniqKey="Ferreira J" first="Joaquim" last="Ferreira">Joaquim Ferreira</name></noRegion></country><country name="Canada"><noRegion><name sortKey="Brotchie, Jonathan M" sort="Brotchie, Jonathan M" uniqKey="Brotchie J" first="Jonathan M." last="Brotchie">Jonathan M. 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