Phase II/III randomized trial of TCH346 in patients with ALS

R. Miller, Walter G Bradley, M. Cudkowicz, J. Hubble, V. Meininger, H. Mitsumoto, D. Moore, H. Pohlmann, D. Sauer, V. Silani, M. Strong, M. Swash, E. Vernotica, Neil Cashman, Andrew Eisen, Charles Krieger, Angela Genge, Sanjay Kalra, John Turnbull, Lucette Lacomblez & 27 others William Camu, Alain Destee, Albert Christian Ludolph, Reinhard Dengler, Thomas Meyer, Adriano Chio, L. H. Van Den Berg, M. De Visser, Francois Vingerhoets, Orla Hardiman, N. Leigh, Jeremy Shefner, William David, Michael Graves, Terry Heiman-Patterson, Hans Neville, Jeffrey Rosenfeld, Mark Bromberg, Andrea Corse, Andrew Waclawik, Erik Pioro, Robert Sufit, Stanley Appel, Robert Pascuzzi, John Kissel, Carlayne Jackson, Richard Barohn

Research output: Contribution to journalArticle

92 Citations (Scopus)

Abstract

BACKGROUND: TCH346 exerts antiapoptotic effects by binding to glyceraldehyde 3-phosphate dehydrogenase (GAPDH) and blocking the apoptotic pathway in which GAPDH is involved. Apoptosis is considered to be a key pathogenic mechanism in neurodegenerative diseases including ALS. METHODS: Patients were randomly assigned in a double-blind fashion to receive either placebo or one of four doses of TCH346 (1.0, 2.5, 7.5, or 15 mg/day) administered orally once daily for at least 24 weeks. The primary outcome measure was the rate of change in the revised ALS functional rating scale (ALSFRS-R). The trial design included a 16-week lead-in phase to determine each patient's rate of disease progression. The between treatment comparison was adjusted for the individual pretreatment rates of progression. The study was powered to detect a 25% reduction in the rate of decline of the ALSFRS-R as compared with placebo. Secondary outcome measures included survival, pulmonary function, and manual muscle testing (MMT). RESULTS: Five hundred ninety-one patients were enrolled at 42 sites in Europe and North America. There were no differences in baseline variables. There were no significant differences between placebo and active treatment groups in the mean rate of decline of the ALSFRS-R or in the secondary outcome measures (survival, pulmonary function, and MMT). CONCLUSION: The trial revealed no evidence of a beneficial effect of TCH346 on disease progression in patients with ALS.

Original languageEnglish
Pages (from-to)776-784
Number of pages9
JournalNeurology
Volume69
Issue number8
DOIs
StatePublished - Aug 1 2007

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Glyceraldehyde-3-Phosphate Dehydrogenases
Placebos
Outcome Assessment (Health Care)
Disease Progression
Muscles
Lung
Survival
North America
Neurodegenerative Diseases
Apoptosis
dibenzo(b,f)oxepin-10-ylmethyl-methyl-prop-2-ynyl-amine
Therapeutics

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Miller, R., Bradley, W. G., Cudkowicz, M., Hubble, J., Meininger, V., Mitsumoto, H., ... Barohn, R. (2007). Phase II/III randomized trial of TCH346 in patients with ALS. Neurology, 69(8), 776-784. https://doi.org/10.1212/01.wnl.0000269676.07319.09

Phase II/III randomized trial of TCH346 in patients with ALS. / Miller, R.; Bradley, Walter G; Cudkowicz, M.; Hubble, J.; Meininger, V.; Mitsumoto, H.; Moore, D.; Pohlmann, H.; Sauer, D.; Silani, V.; Strong, M.; Swash, M.; Vernotica, E.; Cashman, Neil; Eisen, Andrew; Krieger, Charles; Genge, Angela; Kalra, Sanjay; Turnbull, John; Lacomblez, Lucette; Camu, William; Destee, Alain; Ludolph, Albert Christian; Dengler, Reinhard; Meyer, Thomas; Chio, Adriano; Van Den Berg, L. H.; De Visser, M.; Vingerhoets, Francois; Hardiman, Orla; Leigh, N.; Shefner, Jeremy; David, William; Graves, Michael; Heiman-Patterson, Terry; Neville, Hans; Rosenfeld, Jeffrey; Bromberg, Mark; Corse, Andrea; Waclawik, Andrew; Pioro, Erik; Sufit, Robert; Appel, Stanley; Pascuzzi, Robert; Kissel, John; Jackson, Carlayne; Barohn, Richard.

In: Neurology, Vol. 69, No. 8, 01.08.2007, p. 776-784.

Research output: Contribution to journalArticle

Miller, R, Bradley, WG, Cudkowicz, M, Hubble, J, Meininger, V, Mitsumoto, H, Moore, D, Pohlmann, H, Sauer, D, Silani, V, Strong, M, Swash, M, Vernotica, E, Cashman, N, Eisen, A, Krieger, C, Genge, A, Kalra, S, Turnbull, J, Lacomblez, L, Camu, W, Destee, A, Ludolph, AC, Dengler, R, Meyer, T, Chio, A, Van Den Berg, LH, De Visser, M, Vingerhoets, F, Hardiman, O, Leigh, N, Shefner, J, David, W, Graves, M, Heiman-Patterson, T, Neville, H, Rosenfeld, J, Bromberg, M, Corse, A, Waclawik, A, Pioro, E, Sufit, R, Appel, S, Pascuzzi, R, Kissel, J, Jackson, C & Barohn, R 2007, 'Phase II/III randomized trial of TCH346 in patients with ALS', Neurology, vol. 69, no. 8, pp. 776-784. https://doi.org/10.1212/01.wnl.0000269676.07319.09
Miller R, Bradley WG, Cudkowicz M, Hubble J, Meininger V, Mitsumoto H et al. Phase II/III randomized trial of TCH346 in patients with ALS. Neurology. 2007 Aug 1;69(8):776-784. https://doi.org/10.1212/01.wnl.0000269676.07319.09
Miller, R. ; Bradley, Walter G ; Cudkowicz, M. ; Hubble, J. ; Meininger, V. ; Mitsumoto, H. ; Moore, D. ; Pohlmann, H. ; Sauer, D. ; Silani, V. ; Strong, M. ; Swash, M. ; Vernotica, E. ; Cashman, Neil ; Eisen, Andrew ; Krieger, Charles ; Genge, Angela ; Kalra, Sanjay ; Turnbull, John ; Lacomblez, Lucette ; Camu, William ; Destee, Alain ; Ludolph, Albert Christian ; Dengler, Reinhard ; Meyer, Thomas ; Chio, Adriano ; Van Den Berg, L. H. ; De Visser, M. ; Vingerhoets, Francois ; Hardiman, Orla ; Leigh, N. ; Shefner, Jeremy ; David, William ; Graves, Michael ; Heiman-Patterson, Terry ; Neville, Hans ; Rosenfeld, Jeffrey ; Bromberg, Mark ; Corse, Andrea ; Waclawik, Andrew ; Pioro, Erik ; Sufit, Robert ; Appel, Stanley ; Pascuzzi, Robert ; Kissel, John ; Jackson, Carlayne ; Barohn, Richard. / Phase II/III randomized trial of TCH346 in patients with ALS. In: Neurology. 2007 ; Vol. 69, No. 8. pp. 776-784.
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abstract = "BACKGROUND: TCH346 exerts antiapoptotic effects by binding to glyceraldehyde 3-phosphate dehydrogenase (GAPDH) and blocking the apoptotic pathway in which GAPDH is involved. Apoptosis is considered to be a key pathogenic mechanism in neurodegenerative diseases including ALS. METHODS: Patients were randomly assigned in a double-blind fashion to receive either placebo or one of four doses of TCH346 (1.0, 2.5, 7.5, or 15 mg/day) administered orally once daily for at least 24 weeks. The primary outcome measure was the rate of change in the revised ALS functional rating scale (ALSFRS-R). The trial design included a 16-week lead-in phase to determine each patient's rate of disease progression. The between treatment comparison was adjusted for the individual pretreatment rates of progression. The study was powered to detect a 25{\%} reduction in the rate of decline of the ALSFRS-R as compared with placebo. Secondary outcome measures included survival, pulmonary function, and manual muscle testing (MMT). RESULTS: Five hundred ninety-one patients were enrolled at 42 sites in Europe and North America. There were no differences in baseline variables. There were no significant differences between placebo and active treatment groups in the mean rate of decline of the ALSFRS-R or in the secondary outcome measures (survival, pulmonary function, and MMT). CONCLUSION: The trial revealed no evidence of a beneficial effect of TCH346 on disease progression in patients with ALS.",
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T1 - Phase II/III randomized trial of TCH346 in patients with ALS

AU - Miller, R.

AU - Bradley, Walter G

AU - Cudkowicz, M.

AU - Hubble, J.

AU - Meininger, V.

AU - Mitsumoto, H.

AU - Moore, D.

AU - Pohlmann, H.

AU - Sauer, D.

AU - Silani, V.

AU - Strong, M.

AU - Swash, M.

AU - Vernotica, E.

AU - Cashman, Neil

AU - Eisen, Andrew

AU - Krieger, Charles

AU - Genge, Angela

AU - Kalra, Sanjay

AU - Turnbull, John

AU - Lacomblez, Lucette

AU - Camu, William

AU - Destee, Alain

AU - Ludolph, Albert Christian

AU - Dengler, Reinhard

AU - Meyer, Thomas

AU - Chio, Adriano

AU - Van Den Berg, L. H.

AU - De Visser, M.

AU - Vingerhoets, Francois

AU - Hardiman, Orla

AU - Leigh, N.

AU - Shefner, Jeremy

AU - David, William

AU - Graves, Michael

AU - Heiman-Patterson, Terry

AU - Neville, Hans

AU - Rosenfeld, Jeffrey

AU - Bromberg, Mark

AU - Corse, Andrea

AU - Waclawik, Andrew

AU - Pioro, Erik

AU - Sufit, Robert

AU - Appel, Stanley

AU - Pascuzzi, Robert

AU - Kissel, John

AU - Jackson, Carlayne

AU - Barohn, Richard

PY - 2007/8/1

Y1 - 2007/8/1

N2 - BACKGROUND: TCH346 exerts antiapoptotic effects by binding to glyceraldehyde 3-phosphate dehydrogenase (GAPDH) and blocking the apoptotic pathway in which GAPDH is involved. Apoptosis is considered to be a key pathogenic mechanism in neurodegenerative diseases including ALS. METHODS: Patients were randomly assigned in a double-blind fashion to receive either placebo or one of four doses of TCH346 (1.0, 2.5, 7.5, or 15 mg/day) administered orally once daily for at least 24 weeks. The primary outcome measure was the rate of change in the revised ALS functional rating scale (ALSFRS-R). The trial design included a 16-week lead-in phase to determine each patient's rate of disease progression. The between treatment comparison was adjusted for the individual pretreatment rates of progression. The study was powered to detect a 25% reduction in the rate of decline of the ALSFRS-R as compared with placebo. Secondary outcome measures included survival, pulmonary function, and manual muscle testing (MMT). RESULTS: Five hundred ninety-one patients were enrolled at 42 sites in Europe and North America. There were no differences in baseline variables. There were no significant differences between placebo and active treatment groups in the mean rate of decline of the ALSFRS-R or in the secondary outcome measures (survival, pulmonary function, and MMT). CONCLUSION: The trial revealed no evidence of a beneficial effect of TCH346 on disease progression in patients with ALS.

AB - BACKGROUND: TCH346 exerts antiapoptotic effects by binding to glyceraldehyde 3-phosphate dehydrogenase (GAPDH) and blocking the apoptotic pathway in which GAPDH is involved. Apoptosis is considered to be a key pathogenic mechanism in neurodegenerative diseases including ALS. METHODS: Patients were randomly assigned in a double-blind fashion to receive either placebo or one of four doses of TCH346 (1.0, 2.5, 7.5, or 15 mg/day) administered orally once daily for at least 24 weeks. The primary outcome measure was the rate of change in the revised ALS functional rating scale (ALSFRS-R). The trial design included a 16-week lead-in phase to determine each patient's rate of disease progression. The between treatment comparison was adjusted for the individual pretreatment rates of progression. The study was powered to detect a 25% reduction in the rate of decline of the ALSFRS-R as compared with placebo. Secondary outcome measures included survival, pulmonary function, and manual muscle testing (MMT). RESULTS: Five hundred ninety-one patients were enrolled at 42 sites in Europe and North America. There were no differences in baseline variables. There were no significant differences between placebo and active treatment groups in the mean rate of decline of the ALSFRS-R or in the secondary outcome measures (survival, pulmonary function, and MMT). CONCLUSION: The trial revealed no evidence of a beneficial effect of TCH346 on disease progression in patients with ALS.

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