Randomized trial of the triple monoamine reuptake inhibitor NS 2330 (tesofensine) in early Parkinson's disease

Robert A. Hauser, Laurence Salin, Nolwenn Juhel, Victor L. Konyago, Carmel Armon, Danny Bartel, Nicolaas I. Bohnen, Bruce Cleeremans, Cynthia Comella, Warren Davidson, J. Antonnelle De Marcaida, Anthony Dowel, Edward Drasby, Bradley Evans, Enrico Fazzini, Gerald Ferencz, Hubert Fernandez, Jeffrey Friedlander, Susanne Gazda, Mark Guttman & 36 others David Hart, Stuart Isaacson, Alan Jacobs, Joseph Jankovic, Danna Jennings, David King, Louis C. Kirby, Bruce Kohrman, Sandra Kostyk, Michael R. Liebowitz, Michael Lobatz, David Ira Margolin, Ekaterini Markopoulou, John M. Murphy, W. Alvin McElveen, Chi Kin Ng, Margarita Nunez, Sotiriof A. Parashos, John Porter, Emmanuelle Pourcher, Ali Rajput, Ralph Richter, David B. Ross, Harvey D. Schwartz, Carlos Singer, James Stevens, Jon Stoessl, Oksana Suchowersky, James P. Sutton, Mutaz Tabbaa, Daniel Truong, Paul Tuite, Roil I Ann Wallis, Jeannette Wendt, Theresa Zesiewicz, Richard Zweig

Research output: Contribution to journalArticle

40 Citations (Scopus)

Abstract

The objective of this study was to evaluate the efficacy and safety of three daily dosages of the triple monoamine reuptake inhibitor NS 2330 (tesofensine) compared to placebo as monotherapy in early Parkinson's disease (PD). In MPTP (1-methyl 4-phenyl-tetrahydropyridine 1,2,3,6)-lesioned marmosets, dopamine reuptake inhibitors have been demonstrated to reverse parkinsonian signs without evoking established dyskinesia. NS 2330 inhibits reuptake of dopamine, serotonin, and norepinephrine. We performed a proof-of-concept, randomized, double-blind trial of NS 2330. Two hundred sixty-one subjects with PD < 5 years and not receiving dopaminergic treatment were randomly assigned to daily treatment with NS 2330 at 0.25 mg, 0.5 mg, 1.0 mg, or placebo. Adjusted mean difference in total Unified Parkinson's Disease Rating Scale (UPDRS) scores from baseline to week 14 was -0.7 (P = 0.64) in the 0.25-mg group, -1.3 (P = 0.41) in the 0.5-mg group, and -1.7 (P = 0.27) in the 1.0-mg group. The adjusted mean difference in total UPDRS score for the highest dose group (1.0 mg/day) was superior to placebo at week 6 (-3.1; P = 0.02), but this effect was not sustained. NS 2330 was generally well tolerated and the most commonly reported adverse events were constipation, insomnia, and dry mouth. Decreased body weight and elevated heart rate were common in the 1.0-mg dosage group. At the dosages tested, NS 2330 did not provide significantly greater benefit than placebo. It is possible that inhibition of dopamine reuptake alone does not provide clinical benefit in early PD, adequate inhibition of dopamine reuptake was not achieved in this study, or counter-vailing physiologic mechanisms offset the potential benefit.

Original languageEnglish
Pages (from-to)359-365
Number of pages7
JournalMovement Disorders
Volume22
Issue number3
DOIs
StatePublished - Feb 15 2007
Externally publishedYes

Fingerprint

Parkinson Disease
Placebos
Dopamine
Dopamine Uptake Inhibitors
Callithrix
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
Dyskinesias
Sleep Initiation and Maintenance Disorders
Constipation
Mouth
Serotonin
Norepinephrine
Heart Rate
Body Weight
Tesofensine
Safety
Therapeutics
Inhibition (Psychology)

Keywords

  • Clinical trial
  • Dopamine reuptake inhibitor
  • Dopamine transporter
  • Monotherapy
  • NS 2330
  • Parkinson's disease
  • Tesofensine
  • Treatment

ASJC Scopus subject areas

  • Clinical Neurology
  • Neuroscience(all)

Cite this

Hauser, R. A., Salin, L., Juhel, N., Konyago, V. L., Armon, C., Bartel, D., ... Zweig, R. (2007). Randomized trial of the triple monoamine reuptake inhibitor NS 2330 (tesofensine) in early Parkinson's disease. Movement Disorders, 22(3), 359-365. https://doi.org/10.1002/mds.21258

Randomized trial of the triple monoamine reuptake inhibitor NS 2330 (tesofensine) in early Parkinson's disease. / Hauser, Robert A.; Salin, Laurence; Juhel, Nolwenn; Konyago, Victor L.; Armon, Carmel; Bartel, Danny; Bohnen, Nicolaas I.; Cleeremans, Bruce; Comella, Cynthia; Davidson, Warren; De Marcaida, J. Antonnelle; Dowel, Anthony; Drasby, Edward; Evans, Bradley; Fazzini, Enrico; Ferencz, Gerald; Fernandez, Hubert; Friedlander, Jeffrey; Gazda, Susanne; Guttman, Mark; Hart, David; Isaacson, Stuart; Jacobs, Alan; Jankovic, Joseph; Jennings, Danna; King, David; Kirby, Louis C.; Kohrman, Bruce; Kostyk, Sandra; Liebowitz, Michael R.; Lobatz, Michael; Margolin, David Ira; Markopoulou, Ekaterini; Murphy, John M.; McElveen, W. Alvin; Ng, Chi Kin; Nunez, Margarita; Parashos, Sotiriof A.; Porter, John; Pourcher, Emmanuelle; Rajput, Ali; Richter, Ralph; Ross, David B.; Schwartz, Harvey D.; Singer, Carlos; Stevens, James; Stoessl, Jon; Suchowersky, Oksana; Sutton, James P.; Tabbaa, Mutaz; Truong, Daniel; Tuite, Paul; Wallis, Roil I Ann; Wendt, Jeannette; Zesiewicz, Theresa; Zweig, Richard.

In: Movement Disorders, Vol. 22, No. 3, 15.02.2007, p. 359-365.

Research output: Contribution to journalArticle

Hauser, RA, Salin, L, Juhel, N, Konyago, VL, Armon, C, Bartel, D, Bohnen, NI, Cleeremans, B, Comella, C, Davidson, W, De Marcaida, JA, Dowel, A, Drasby, E, Evans, B, Fazzini, E, Ferencz, G, Fernandez, H, Friedlander, J, Gazda, S, Guttman, M, Hart, D, Isaacson, S, Jacobs, A, Jankovic, J, Jennings, D, King, D, Kirby, LC, Kohrman, B, Kostyk, S, Liebowitz, MR, Lobatz, M, Margolin, DI, Markopoulou, E, Murphy, JM, McElveen, WA, Ng, CK, Nunez, M, Parashos, SA, Porter, J, Pourcher, E, Rajput, A, Richter, R, Ross, DB, Schwartz, HD, Singer, C, Stevens, J, Stoessl, J, Suchowersky, O, Sutton, JP, Tabbaa, M, Truong, D, Tuite, P, Wallis, RIA, Wendt, J, Zesiewicz, T & Zweig, R 2007, 'Randomized trial of the triple monoamine reuptake inhibitor NS 2330 (tesofensine) in early Parkinson's disease', Movement Disorders, vol. 22, no. 3, pp. 359-365. https://doi.org/10.1002/mds.21258
Hauser, Robert A. ; Salin, Laurence ; Juhel, Nolwenn ; Konyago, Victor L. ; Armon, Carmel ; Bartel, Danny ; Bohnen, Nicolaas I. ; Cleeremans, Bruce ; Comella, Cynthia ; Davidson, Warren ; De Marcaida, J. Antonnelle ; Dowel, Anthony ; Drasby, Edward ; Evans, Bradley ; Fazzini, Enrico ; Ferencz, Gerald ; Fernandez, Hubert ; Friedlander, Jeffrey ; Gazda, Susanne ; Guttman, Mark ; Hart, David ; Isaacson, Stuart ; Jacobs, Alan ; Jankovic, Joseph ; Jennings, Danna ; King, David ; Kirby, Louis C. ; Kohrman, Bruce ; Kostyk, Sandra ; Liebowitz, Michael R. ; Lobatz, Michael ; Margolin, David Ira ; Markopoulou, Ekaterini ; Murphy, John M. ; McElveen, W. Alvin ; Ng, Chi Kin ; Nunez, Margarita ; Parashos, Sotiriof A. ; Porter, John ; Pourcher, Emmanuelle ; Rajput, Ali ; Richter, Ralph ; Ross, David B. ; Schwartz, Harvey D. ; Singer, Carlos ; Stevens, James ; Stoessl, Jon ; Suchowersky, Oksana ; Sutton, James P. ; Tabbaa, Mutaz ; Truong, Daniel ; Tuite, Paul ; Wallis, Roil I Ann ; Wendt, Jeannette ; Zesiewicz, Theresa ; Zweig, Richard. / Randomized trial of the triple monoamine reuptake inhibitor NS 2330 (tesofensine) in early Parkinson's disease. In: Movement Disorders. 2007 ; Vol. 22, No. 3. pp. 359-365.
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AU - Hauser, Robert A.

AU - Salin, Laurence

AU - Juhel, Nolwenn

AU - Konyago, Victor L.

AU - Armon, Carmel

AU - Bartel, Danny

AU - Bohnen, Nicolaas I.

AU - Cleeremans, Bruce

AU - Comella, Cynthia

AU - Davidson, Warren

AU - De Marcaida, J. Antonnelle

AU - Dowel, Anthony

AU - Drasby, Edward

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AU - Fernandez, Hubert

AU - Friedlander, Jeffrey

AU - Gazda, Susanne

AU - Guttman, Mark

AU - Hart, David

AU - Isaacson, Stuart

AU - Jacobs, Alan

AU - Jankovic, Joseph

AU - Jennings, Danna

AU - King, David

AU - Kirby, Louis C.

AU - Kohrman, Bruce

AU - Kostyk, Sandra

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AU - Margolin, David Ira

AU - Markopoulou, Ekaterini

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AU - Ng, Chi Kin

AU - Nunez, Margarita

AU - Parashos, Sotiriof A.

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AU - Pourcher, Emmanuelle

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AU - Ross, David B.

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AU - Singer, Carlos

AU - Stevens, James

AU - Stoessl, Jon

AU - Suchowersky, Oksana

AU - Sutton, James P.

AU - Tabbaa, Mutaz

AU - Truong, Daniel

AU - Tuite, Paul

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AU - Wendt, Jeannette

AU - Zesiewicz, Theresa

AU - Zweig, Richard

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N2 - The objective of this study was to evaluate the efficacy and safety of three daily dosages of the triple monoamine reuptake inhibitor NS 2330 (tesofensine) compared to placebo as monotherapy in early Parkinson's disease (PD). In MPTP (1-methyl 4-phenyl-tetrahydropyridine 1,2,3,6)-lesioned marmosets, dopamine reuptake inhibitors have been demonstrated to reverse parkinsonian signs without evoking established dyskinesia. NS 2330 inhibits reuptake of dopamine, serotonin, and norepinephrine. We performed a proof-of-concept, randomized, double-blind trial of NS 2330. Two hundred sixty-one subjects with PD < 5 years and not receiving dopaminergic treatment were randomly assigned to daily treatment with NS 2330 at 0.25 mg, 0.5 mg, 1.0 mg, or placebo. Adjusted mean difference in total Unified Parkinson's Disease Rating Scale (UPDRS) scores from baseline to week 14 was -0.7 (P = 0.64) in the 0.25-mg group, -1.3 (P = 0.41) in the 0.5-mg group, and -1.7 (P = 0.27) in the 1.0-mg group. The adjusted mean difference in total UPDRS score for the highest dose group (1.0 mg/day) was superior to placebo at week 6 (-3.1; P = 0.02), but this effect was not sustained. NS 2330 was generally well tolerated and the most commonly reported adverse events were constipation, insomnia, and dry mouth. Decreased body weight and elevated heart rate were common in the 1.0-mg dosage group. At the dosages tested, NS 2330 did not provide significantly greater benefit than placebo. It is possible that inhibition of dopamine reuptake alone does not provide clinical benefit in early PD, adequate inhibition of dopamine reuptake was not achieved in this study, or counter-vailing physiologic mechanisms offset the potential benefit.

AB - The objective of this study was to evaluate the efficacy and safety of three daily dosages of the triple monoamine reuptake inhibitor NS 2330 (tesofensine) compared to placebo as monotherapy in early Parkinson's disease (PD). In MPTP (1-methyl 4-phenyl-tetrahydropyridine 1,2,3,6)-lesioned marmosets, dopamine reuptake inhibitors have been demonstrated to reverse parkinsonian signs without evoking established dyskinesia. NS 2330 inhibits reuptake of dopamine, serotonin, and norepinephrine. We performed a proof-of-concept, randomized, double-blind trial of NS 2330. Two hundred sixty-one subjects with PD < 5 years and not receiving dopaminergic treatment were randomly assigned to daily treatment with NS 2330 at 0.25 mg, 0.5 mg, 1.0 mg, or placebo. Adjusted mean difference in total Unified Parkinson's Disease Rating Scale (UPDRS) scores from baseline to week 14 was -0.7 (P = 0.64) in the 0.25-mg group, -1.3 (P = 0.41) in the 0.5-mg group, and -1.7 (P = 0.27) in the 1.0-mg group. The adjusted mean difference in total UPDRS score for the highest dose group (1.0 mg/day) was superior to placebo at week 6 (-3.1; P = 0.02), but this effect was not sustained. NS 2330 was generally well tolerated and the most commonly reported adverse events were constipation, insomnia, and dry mouth. Decreased body weight and elevated heart rate were common in the 1.0-mg dosage group. At the dosages tested, NS 2330 did not provide significantly greater benefit than placebo. It is possible that inhibition of dopamine reuptake alone does not provide clinical benefit in early PD, adequate inhibition of dopamine reuptake was not achieved in this study, or counter-vailing physiologic mechanisms offset the potential benefit.

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