A randomized, placebo-controlled trial of topiramate in amyotrophic lateral sclerosis

Merit E. Cudkowicz, J. M. Shefner, D. A. Schoenfeld, R. H. Brown, H. Johnson, M. Qureshi, M. Jacobs, Jeffrey D Rothstein, S. H. Appel, R. M. Pascuzzi, T. D. Heiman-Patterson, P. D. Donofrio, W. S. David, J. A. Russell, R. Tandan, E. P. Pioro, K. J. Felice, J. Rosenfeld, R. N. Mandler, G. M. SachsW. G. Bradley, E. M. Raynor, G. D. Baquis, J. M. Belsh, S. Novella, J. Goldstein, J. Hulihan

Research output: Contribution to journalArticle

Abstract

Objective: To determine if long-term topiramate therapy is safe and slows disease progression in patients with ALS. Methods: A double-blind, placebo-controlled, multicenter randomized clinical trial was conducted. Participants with ALS (n = 296) were randomized (2:1) to receive topiramate (maximum tolerated dose up to 800 mg/day) or placebo for 12 months. The primary outcome measure was the rate of change in upper extremity motor function as measured by the maximum voluntary isometric contraction (MVIC) strength of eight arm muscle groups. Secondary endpoints included safety and the rate of decline of forced vital capacity (FVC), grip strength, ALS functional rating scale (ALSFRS), and survival. Results: Patients treated with topiramate showed a faster decrease in arm strength (33.3%) during 12 months (0.0997 vs 0.0748 unit decline/month, p = 0.012). Topiramate did not significantly alter the decline in FVC and ALSFRS or affect survival. Topiramate was associated with an increased frequency of anorexia, depression, diarrhea, ecchymosis, nausea, kidney calculus, paresthesia, taste perversion, thinking abnormalities, weight loss, and abnormal blood clotting (pulmonary embolism and deep venous thrombosis). Conclusions: At the dose studied, topiramate did not have a beneficial effect for patients with ALS. High-dose topiramate treatment was associated with a faster rate of decline in muscle strength as measured by MVIC and with an increased risk for several adverse events in patients with ALS. Given the lack of efficacy and large number of adverse effects, further studies of topiramate at a dose of 800 mg or maximum tolerated dose up to 800 mg/day are not warranted.

Original languageEnglish (US)
Pages (from-to)456-464
Number of pages9
JournalNeurology
Volume61
Issue number4
StatePublished - Aug 26 2003

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Amyotrophic Lateral Sclerosis
Randomized Controlled Trials
Placebos
Isometric Contraction
Maximum Tolerated Dose
Vital Capacity
Arm
Ecchymosis
Kidney Calculi
Survival
topiramate
Paresthesia
Muscle Strength
Anorexia
Blood Coagulation
Hand Strength
Pulmonary Embolism
Double-Blind Method
Upper Extremity
Venous Thrombosis

ASJC Scopus subject areas

  • Neuroscience(all)

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Cudkowicz, M. E., Shefner, J. M., Schoenfeld, D. A., Brown, R. H., Johnson, H., Qureshi, M., ... Hulihan, J. (2003). A randomized, placebo-controlled trial of topiramate in amyotrophic lateral sclerosis. Neurology, 61(4), 456-464.

A randomized, placebo-controlled trial of topiramate in amyotrophic lateral sclerosis. / Cudkowicz, Merit E.; Shefner, J. M.; Schoenfeld, D. A.; Brown, R. H.; Johnson, H.; Qureshi, M.; Jacobs, M.; Rothstein, Jeffrey D; Appel, S. H.; Pascuzzi, R. M.; Heiman-Patterson, T. D.; Donofrio, P. D.; David, W. S.; Russell, J. A.; Tandan, R.; Pioro, E. P.; Felice, K. J.; Rosenfeld, J.; Mandler, R. N.; Sachs, G. M.; Bradley, W. G.; Raynor, E. M.; Baquis, G. D.; Belsh, J. M.; Novella, S.; Goldstein, J.; Hulihan, J.

In: Neurology, Vol. 61, No. 4, 26.08.2003, p. 456-464.

Research output: Contribution to journalArticle

Cudkowicz, ME, Shefner, JM, Schoenfeld, DA, Brown, RH, Johnson, H, Qureshi, M, Jacobs, M, Rothstein, JD, Appel, SH, Pascuzzi, RM, Heiman-Patterson, TD, Donofrio, PD, David, WS, Russell, JA, Tandan, R, Pioro, EP, Felice, KJ, Rosenfeld, J, Mandler, RN, Sachs, GM, Bradley, WG, Raynor, EM, Baquis, GD, Belsh, JM, Novella, S, Goldstein, J & Hulihan, J 2003, 'A randomized, placebo-controlled trial of topiramate in amyotrophic lateral sclerosis', Neurology, vol. 61, no. 4, pp. 456-464.
Cudkowicz ME, Shefner JM, Schoenfeld DA, Brown RH, Johnson H, Qureshi M et al. A randomized, placebo-controlled trial of topiramate in amyotrophic lateral sclerosis. Neurology. 2003 Aug 26;61(4):456-464.
Cudkowicz, Merit E. ; Shefner, J. M. ; Schoenfeld, D. A. ; Brown, R. H. ; Johnson, H. ; Qureshi, M. ; Jacobs, M. ; Rothstein, Jeffrey D ; Appel, S. H. ; Pascuzzi, R. M. ; Heiman-Patterson, T. D. ; Donofrio, P. D. ; David, W. S. ; Russell, J. A. ; Tandan, R. ; Pioro, E. P. ; Felice, K. J. ; Rosenfeld, J. ; Mandler, R. N. ; Sachs, G. M. ; Bradley, W. G. ; Raynor, E. M. ; Baquis, G. D. ; Belsh, J. M. ; Novella, S. ; Goldstein, J. ; Hulihan, J. / A randomized, placebo-controlled trial of topiramate in amyotrophic lateral sclerosis. In: Neurology. 2003 ; Vol. 61, No. 4. pp. 456-464.
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title = "A randomized, placebo-controlled trial of topiramate in amyotrophic lateral sclerosis",
abstract = "Objective: To determine if long-term topiramate therapy is safe and slows disease progression in patients with ALS. Methods: A double-blind, placebo-controlled, multicenter randomized clinical trial was conducted. Participants with ALS (n = 296) were randomized (2:1) to receive topiramate (maximum tolerated dose up to 800 mg/day) or placebo for 12 months. The primary outcome measure was the rate of change in upper extremity motor function as measured by the maximum voluntary isometric contraction (MVIC) strength of eight arm muscle groups. Secondary endpoints included safety and the rate of decline of forced vital capacity (FVC), grip strength, ALS functional rating scale (ALSFRS), and survival. Results: Patients treated with topiramate showed a faster decrease in arm strength (33.3{\%}) during 12 months (0.0997 vs 0.0748 unit decline/month, p = 0.012). Topiramate did not significantly alter the decline in FVC and ALSFRS or affect survival. Topiramate was associated with an increased frequency of anorexia, depression, diarrhea, ecchymosis, nausea, kidney calculus, paresthesia, taste perversion, thinking abnormalities, weight loss, and abnormal blood clotting (pulmonary embolism and deep venous thrombosis). Conclusions: At the dose studied, topiramate did not have a beneficial effect for patients with ALS. High-dose topiramate treatment was associated with a faster rate of decline in muscle strength as measured by MVIC and with an increased risk for several adverse events in patients with ALS. Given the lack of efficacy and large number of adverse effects, further studies of topiramate at a dose of 800 mg or maximum tolerated dose up to 800 mg/day are not warranted.",
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T1 - A randomized, placebo-controlled trial of topiramate in amyotrophic lateral sclerosis

AU - Cudkowicz, Merit E.

AU - Shefner, J. M.

AU - Schoenfeld, D. A.

AU - Brown, R. H.

AU - Johnson, H.

AU - Qureshi, M.

AU - Jacobs, M.

AU - Rothstein, Jeffrey D

AU - Appel, S. H.

AU - Pascuzzi, R. M.

AU - Heiman-Patterson, T. D.

AU - Donofrio, P. D.

AU - David, W. S.

AU - Russell, J. A.

AU - Tandan, R.

AU - Pioro, E. P.

AU - Felice, K. J.

AU - Rosenfeld, J.

AU - Mandler, R. N.

AU - Sachs, G. M.

AU - Bradley, W. G.

AU - Raynor, E. M.

AU - Baquis, G. D.

AU - Belsh, J. M.

AU - Novella, S.

AU - Goldstein, J.

AU - Hulihan, J.

PY - 2003/8/26

Y1 - 2003/8/26

N2 - Objective: To determine if long-term topiramate therapy is safe and slows disease progression in patients with ALS. Methods: A double-blind, placebo-controlled, multicenter randomized clinical trial was conducted. Participants with ALS (n = 296) were randomized (2:1) to receive topiramate (maximum tolerated dose up to 800 mg/day) or placebo for 12 months. The primary outcome measure was the rate of change in upper extremity motor function as measured by the maximum voluntary isometric contraction (MVIC) strength of eight arm muscle groups. Secondary endpoints included safety and the rate of decline of forced vital capacity (FVC), grip strength, ALS functional rating scale (ALSFRS), and survival. Results: Patients treated with topiramate showed a faster decrease in arm strength (33.3%) during 12 months (0.0997 vs 0.0748 unit decline/month, p = 0.012). Topiramate did not significantly alter the decline in FVC and ALSFRS or affect survival. Topiramate was associated with an increased frequency of anorexia, depression, diarrhea, ecchymosis, nausea, kidney calculus, paresthesia, taste perversion, thinking abnormalities, weight loss, and abnormal blood clotting (pulmonary embolism and deep venous thrombosis). Conclusions: At the dose studied, topiramate did not have a beneficial effect for patients with ALS. High-dose topiramate treatment was associated with a faster rate of decline in muscle strength as measured by MVIC and with an increased risk for several adverse events in patients with ALS. Given the lack of efficacy and large number of adverse effects, further studies of topiramate at a dose of 800 mg or maximum tolerated dose up to 800 mg/day are not warranted.

AB - Objective: To determine if long-term topiramate therapy is safe and slows disease progression in patients with ALS. Methods: A double-blind, placebo-controlled, multicenter randomized clinical trial was conducted. Participants with ALS (n = 296) were randomized (2:1) to receive topiramate (maximum tolerated dose up to 800 mg/day) or placebo for 12 months. The primary outcome measure was the rate of change in upper extremity motor function as measured by the maximum voluntary isometric contraction (MVIC) strength of eight arm muscle groups. Secondary endpoints included safety and the rate of decline of forced vital capacity (FVC), grip strength, ALS functional rating scale (ALSFRS), and survival. Results: Patients treated with topiramate showed a faster decrease in arm strength (33.3%) during 12 months (0.0997 vs 0.0748 unit decline/month, p = 0.012). Topiramate did not significantly alter the decline in FVC and ALSFRS or affect survival. Topiramate was associated with an increased frequency of anorexia, depression, diarrhea, ecchymosis, nausea, kidney calculus, paresthesia, taste perversion, thinking abnormalities, weight loss, and abnormal blood clotting (pulmonary embolism and deep venous thrombosis). Conclusions: At the dose studied, topiramate did not have a beneficial effect for patients with ALS. High-dose topiramate treatment was associated with a faster rate of decline in muscle strength as measured by MVIC and with an increased risk for several adverse events in patients with ALS. Given the lack of efficacy and large number of adverse effects, further studies of topiramate at a dose of 800 mg or maximum tolerated dose up to 800 mg/day are not warranted.

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