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.
Get full access to this article
View all available purchase options and get full access to this article.
Supplementary Material
File (e1.doc)
- Download
- 19.50 KB
References
1.
Rowland LP. Merritt’s Textbook of Neurology, 9th ed. Philadelphia: Williams and Wilkins, 1995.
2.
Munsat TL, Andres PL, Finison L, Conlon T, Thibodeau L. The natural history of motoneuron loss in ALS. Neurology . 1988; 38: 452–458.
3.
Rothstein JD, Martin LJ, Kuncl RW. Decreased glutamate transport by the brain and spinal cord in amyotrophic lateral sclerosis. N Engl J Med . 1992; 236: 1464–1468.
4.
Rothstein JD, Jin L, Dykes-Hoberg M, Kuncl RW. Chronic inhibition of glutamate uptake produces a model of slow motor neuron toxicity. Proc Natl Acad Sci USA . 1993; 90: 6591–6595.
5.
Rothstein J, Van Kammen M, Levey A, Martin L, Kuncl R. Selective loss of glial glutamate transporter GLT-1 in amyotrophic lateral sclerosis. Ann Neurol . 1995; 38: 73–84.
6.
Rothstein J. Excitotoxic mechanisms in the pathogenesis of amyotrophic lateral sclerosis. In: Serratrice G, Munsat T, eds. Pathogenesis and Therapy of Amyotrophic Lateral Sclerosis. Philadelphia: Lippincott-Raven Publishers, 1995.
7.
Rothstein J, Dykes-Hoberg M, Pardo C, et al. Knockout of glutamate transporters reveals a major role for astroglial transport in excitotoxicity and clearance of glutamate. Neuron . 1996; 16: 675–686.
8.
Sasaki S, Maruyama S, Yamane K, Sakuma H, Takeishi M. Ultrastructure of swollen proximal axons of anterior horn neurons in motor neuron disease. J Neurol Sci . 1990; 97: 233–240.
9.
Siklos L, Engelhardt J, Harati Y, Smith R, Joo F, Appel S. Ultrastructural evidence for altered calcium in motor nerve terminals in amyotrophic lateral sclerosis. Ann Neurol . 1996; 39: 203–219.
10.
Wiedemann F, Winkler K, Kuznetsov A, et al. Impairment of mitochondrial function in skeletal muscle of patients with amyotrophic lateral sclerosis. J Neurol Sci . 1998; 156: 65–72.
11.
Masui Y, Mozai T, Kakehi K. Functional and morphometric study of the liver in motor neuron disease. J Neurol . 1985; 232: 15–19.
12.
Rosen DR, Siddique T, Patterson D, et al. Mutations in Cu/Zn superoxide dismutase are associated with familial amyotrophic lateral sclerosis. Nature . 1993; 362: 59–62.
13.
Ferrante R, Browne S, Shinobu L, et al. Evidence of increased oxidative damage in both sporadic and familial ALS. J Neurochem . 1997; 69: 2064–2074.
14.
Carriedo S, Yin H, Lamberta R, Weiss J. In vitro kainate injury to large SMI-32+ spinal neurons is Ca2+ dependent. Neuroreport . 1996; 6: 945–948.
15.
Hugon J, Vallet J, Spencer P, Leboutet M, Barthe D. Kainic acid induces early and delayed degenerative neuronal changes in rat spinal cord. Neurosci Lett . 1989; 104: 258–262.
16.
Pascuzzi R. Presented at the 10th International Symposium on ALS and Motor Neuron Disease; November 2000; Arhus.
17.
Skradski S, White H. Topiramate blocks kainate-evoked cobalt influx into cultured neurons. Epilepsia . 2000; 41 (suppl 1): S45–S47.
18.
Maragakis N, Jackson M, Ganel R, Rothstein J. Topiramate protects against motor neuron degeneration in organotypic spinal cord cultures but not in G93A SOD1 transgenic mice. Neurosci Lett . 2003; I338: 107–110.
19.
Brooks B. El Escorial World Federation of Neurology criteria for the diagnosis of amyotrophic lateral sclerosis. Subcommittee on Motor Neuron Diseases/Amyotrophic Lateral Sclerosis of the World Federation of Neurology Research Group on Neuromuscular Diseases and the El Escorial “Clinical limits of amyotrophic lateral sclerosis”. J Neurol Sci . 1994; 124 (suppl): 96–107.
20.
Andres P, Hedlund W, Finison L, Conlon T, Felmus M, Munsat T. Quantitative motor assessment in amyotrophic lateral sclerosis. Neurology . 1986; 36: 937–941.
21.
Andres PL, Thibodeau LM, Finison LJ, Munsat TL. Quantitative assessment of neuromuscular deficit in ALS. Neurol Clin . 1987; 5: 125–141.
22.
Miller R, Moore D, Young L, et al. Placebo-controlled trial of gabapentin in patients with amyotrophic lateral sclerosis. Neurology . 1996; 47: 1383–1388.
23.
Miller RG, Moore DH, Gelinas DF, et al. Phase III randomized trial of gabapentin in patients with amyotrophic lateral sclerosis. Neurology . 2001; 56: 843–848.
24.
Cedarbaum J. The amyotrophic lateral sclerosis functional rating scale (ALSFRS). Arch Neurol . 1996; 53: 141–147.
25.
Schoenfeld D. Analysis of categorical data: logistic models. In: Miké V, Stanley K, eds. Statistics in Medical Research. New York: John Wiley and Sons, 1982: 432–454.
26.
Finkelstein D, Schoenfeld D. Combining mortality and longitudinal measures in clinical trials. Stat Med . 1999; 18: 1341–1354.
27.
Miller R, Petajan J, Wilson W, et al. A placebo-controlled trial of recombinant human ciliary neurotrophic (rhCNTF) factor in amyotrophic lateral sclerosis. Ann Neurol . 1996; 39: 256–260.
28.
Rubin D. Inference and missing data. Biometrika . 1976; 63: 581–590.
29.
Smith-Swintosky V, Zhao B, Shank R, Plata-Salaman C. Topiramate promotes neurite outgrowth and recovery of function after nerve injury. Neuro Report . 2001; 12: 1031–1034.
Information & Authors
Information
Published In
Neurology®
Volume 61 • Number 4 • August 26, 2003
Pages: 456-464
Copyright
© 2003.
Publication History
Received: November 16, 2002
Accepted: June 5, 2003
Published online: August 25, 2003
Published in print: August 26, 2003
Authors
Metrics & Citations
Metrics
Citations
Download Citations
If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Select your manager software from the list below and click Download.
Cited By
- Amyotrofik Lateral Skleroz Patofizyolojisi ve Tedavi YaklaşımlarıAn Evaluation of Amyotrophic Lateral Sclerosis and Current Situation in Its Treatment, Hacettepe University Journal of the Faculty of Pharmacy, (2023).https://doi.org/10.52794/hujpharm.1064372
- Randomized, double-blind, placebo-controlled trial of arimoclomol in rapidly progressive SOD1 ALS, Neurology, 90, 7, (e565-e574), (2023)./doi/10.1212/WNL.0000000000004960
- Challenges and opportunities in clinical trials for spinal muscular atrophy, Neurology, 65, 9, (1352-1357), (2023)./doi/10.1212/01.wnl.0000183282.10946.c7
- Hopes and concerns regarding the implementation of expanded access protocols in amyotrophic lateral sclerosis, Muscle & Nerve, 67, 6, (433-435), (2023).https://doi.org/10.1002/mus.27828
- Therapeutic targeting of ALS pathways: Refocusing an incomplete picture , Annals of Clinical and Translational Neurology, (2023).https://doi.org/10.1002/acn3.51887
- Comprehensive Research on Past and Future Therapeutic Strategies Devoted to Treatment of Amyotrophic Lateral Sclerosis, International Journal of Molecular Sciences, 23, 5, (2400), (2022).https://doi.org/10.3390/ijms23052400
- Impact of mode of training and recertification on ALSFRS-R rater performance, Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, 24, 3-4, (289-294), (2022).https://doi.org/10.1080/21678421.2022.2149344
- Treatment and Management of Adult Motor Neuron Diseases, Neuromuscular Disorders, (248-260), (2022).https://doi.org/10.1016/B978-0-323-71317-7.00012-3
- Glutamate-Based Treatment for Amyotrophic Lateral Sclerosis/Motor Neuron Disease, Glutamate and Neuropsychiatric Disorders, (359-380), (2022).https://doi.org/10.1007/978-3-030-87480-3_12
- Amyotrophic Lateral Sclerosis Clinical Trials and Interpretation of Functional End Points and Fluid Biomarkers, JAMA Neurology, 79, 12, (1312), (2022).https://doi.org/10.1001/jamaneurol.2022.3282
- See more
Loading...
View Options
Get Access
Login options
Check if you have access through your login credentials or your institution to get full access on this article.
Personal login Institutional LoginPurchase Options
Purchase this article to get full access to it.