Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Opinion
  • Published:

How can we improve clinical trials in amyotrophic lateral sclerosis?

Abstract

Since the approval of riluzole for the treatment of amyotrophic lateral sclerosis (ALS) 17 years ago, more than 30 large clinical trials have been conducted, but none has proved successful. The failure to translate positive preclinical results into the clinical setting raises questions about the validity of the rodent model that is used to study ALS, and about the quality of both preclinical and clinical studies. However, the greatest challenge is the disease itself as, with rare exceptions, the causes are unknown. In this Perspectives article, we highlight key issues related to the pathophysiology, preclinical studies and clinical trials that should be addressed in the future. These areas include the relationships between different disease mechanisms, the challenges presented by the heterogeneity of the disease, and the need for early intervention, optimal dose selection and effective biomarkers.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

References

  1. Swash, M. We have a problem: why have ALS trials been negative? Amyotroph. Lateral Scler. 8, 259 (2007).

    Article  Google Scholar 

  2. Swash, M. Lithium time-to-event trial in amyotrophic lateral sclerosis stops early for futility. Lancet Neurol. 9, 449–451 (2010).

    Article  Google Scholar 

  3. Aggarwal, S. & Cudkowicz, M. ALS drug development: reflections from the past and a way forward. Neurotherapeutics 5, 516–527 (2008).

    Article  CAS  Google Scholar 

  4. Ludolph, A. C. et al. Guidelines for preclinical animal research in ALS/MND: a consensus meeting. Amyotroph. Lateral Scler. 11, 38–45 (2010).

    Article  Google Scholar 

  5. Mitsumoto, H. et al. Randomized control trials in ALS: lessons learned. Amyotroph. Lateral Scler. Other Motor Neuron Disord. 5 (Suppl. 1), 8–13 (2004).

    Article  CAS  Google Scholar 

  6. Rothstein, J. D. Current hypotheses for the underlying biology of amyotrophic lateral sclerosis. Ann Neurol. 65 (Suppl. 1), S3–S9 (2009).

    Article  CAS  Google Scholar 

  7. Boillée, S., Vande Velde, C. & Cleveland, D. W. ALS: a disease of motor neurons and their nonneuronal neighbors. Neuron 52, 39–59 (2006).

    Article  Google Scholar 

  8. Ravits, J., Paul, P. & Jorg, C. Focality of upper and lower motor neuron degeneration at the clinical onset of ALS. Neurology 68, 1571–1575 (2007).

    Article  Google Scholar 

  9. Johnson, K. A. & Brown, P. H. Drug development for cancer chemoprevention: focus on molecular targets. Semin. Oncol. 37, 345–358 (2010).

    Article  CAS  Google Scholar 

  10. Sreeramoju, P. & Libutti, S. K. Strategies for targeting tumors and tumor vasculature for cancer therapy. Adv. Genet. 69, 135–152 (2010).

    Article  CAS  Google Scholar 

  11. Glass, C. K., Saijo, K., Winner, B., Marchetto, M. C. & Gage, F. H. Mechanisms underlying inflammation in neurodegeneration. Cell 140, 918–934 (2010).

    Article  CAS  Google Scholar 

  12. Schwartz, M. & Shechter, R. Systemic inflammatory cells fight off neurodegenerative disease. Nat. Rev. Neurol. 6, 405–410 (2010).

    Article  CAS  Google Scholar 

  13. Gao, H. M. & Hong, J. S. Gene–environment interactions: key to unraveling the mystery of Parkinson's disease. Prog. Neurobiol. 94, 1–19 (2011).

    Article  Google Scholar 

  14. Postuma, R. B. & Montplaisir, J. Predicting Parkinson's disease—why, when, and how? Parkinsonism Relat. Disord. 15 (Suppl. 3), S105–S109 (2009).

    Article  Google Scholar 

  15. Aluise, C. D. et al. Preclinical Alzheimer disease: brain oxidative stress, Aβ peptide and proteomics. Neurobiol. Dis. 39, 221–228 (2010).

    Article  CAS  Google Scholar 

  16. Elias, M. F. et al. The preclinical phase of Alzheimer disease: a 22-year prospective study of the Framingham Cohort. Arch. Neurol. 57, 808–813 (2000).

    Article  CAS  Google Scholar 

  17. Berg, D. Biomarkers for the early detection of Parkinson's and Alzheimer's disease. Neurodegener. Dis. 5, 133–136 (2008).

    Article  Google Scholar 

  18. Swash, M. & Ingram, D. Preclinical and subclinical events in motor neuron disease. J. Neurol. Neurosurg. Psychiatry 51, 165–168 (1988).

    Article  CAS  Google Scholar 

  19. Aggarwal, A. & Nicholson, G. Detection of preclinical motor neurone loss in SOD1 mutation carriers using motor unit number estimation. J. Neurol. Neurosurg. Psychiatry 73, 199–201 (2002).

    Article  CAS  Google Scholar 

  20. Guégan, C. & Przedborski, S. Programmed cell death in amyotrophic lateral sclerosis. J. Clin. Invest. 111, 153–161 (2003).

    Article  Google Scholar 

  21. Banerjee, R., Beal, M. F. & Thomas, B. Autophagy in neurodegenerative disorders: pathogenic roles and therapeutic implications. Trends Neurosci. 33, 541–549 (2010).

    Article  CAS  Google Scholar 

  22. Gurney, M. E. The use of transgenic mouse models of amyotrophic lateral sclerosis in preclinical drug studies. J. Neurol. Sci. 152 (Suppl. 1), S67–S73 (1997).

    Article  CAS  Google Scholar 

  23. Scott, S. et al. Design, power, and interpretation of studies in the standard murine model of ALS. Amyotroph. Lateral Scler. 9, 4–15 (2008).

    Article  CAS  Google Scholar 

  24. Milane, A. et al. Brain and plasma riluzole pharmacokinetics: effect of minocycline combination. J. Pharm. Pharm. Sci. 12, 209–217 (2009).

    Article  CAS  Google Scholar 

  25. Leigh, P. N., Meininger, V., Bensimon, G., Cudkowicz, M. & Robberecht W. Minocycline for patients with ALS. Lancet Neurol. 7, 119–120 (2008).

    Article  Google Scholar 

  26. Swarup, V. & Julien, J. P. ALS pathogenesis: recent insights from genetics and mouse models. Prog. Neuropsychopharmacol. Biol. Psychiatry 35, 363–369 (2011).

    Article  CAS  Google Scholar 

  27. Kabashi, E. et al. Gain and loss of function of ALS-related mutations of TARDBP (TDP-43) cause motor deficits in vivo. Hum. Mol. Genet. 19, 671–683 (2010).

    Article  CAS  Google Scholar 

  28. Meininger, V. et al. Efficacy and safety of xaliproden in amyotrophic lateral sclerosis: results of two phase III trials. Amyotroph. Lateral Scler. Other Motor Neuron Disord. 5, 107–117 (2004).

    Article  CAS  Google Scholar 

  29. Miller, R. et al. Phase II/III randomized trial of TCH346 in patients with ALS. Neurology 69, 776–784 (2007).

    Article  CAS  Google Scholar 

  30. Meininger, V. et al. Pentoxifylline European Group. Pentoxifylline in ALS: a double-blind, randomized, multicenter, placebo-controlled trial. Neurology 66, 88–92 (2006).

    Article  CAS  Google Scholar 

  31. Miller, R. G. et al. A placebo-controlled trial of recombinant human ciliary neurotrophic (rhCNTF) factor in amyotrophic lateral sclerosis. rhCNTF ALS Study Group. Ann. Neurol. 39, 256–260 (1996).

    Article  CAS  Google Scholar 

  32. [No authors listed] A controlled trial of recombinant methionyl human BDNF in ALS: the BDNF Study Group (Phase III). Neurology 52, 1427–1433 (1999).

  33. Sorenson, E. J. et al. Subcutaneous IGF-1 is not beneficial in 2-year ALS trial. Neurology 71, 1770–1775 (2008).

    Article  CAS  Google Scholar 

  34. Cudkowicz, M. E. et al. A randomized, placebo-controlled trial of topiramate in amyotrophic lateral sclerosis. Neurology 6, 456–464 (2003).

    Article  Google Scholar 

  35. Miller, R. G. et al. Phase III randomized trial of gabapentin in patients with amyotrophic lateral sclerosis. Neurology 56, 843–848 (2001).

    Article  CAS  Google Scholar 

  36. Gordon, P. H. et al. Efficacy of minocycline in patients with amyotrophic lateral sclerosis: a phase III randomised trial. Lancet Neurol. 6, 1045–1053 (2007).

    Article  CAS  Google Scholar 

  37. Meininger, V. et al. Glatiramer acetate has no impact on disease progression in ALS at 40 mg/day: a double-blind, randomized, multicentre, placebo-controlled trial. Amyotroph. Lateral Scler. 10, 378–383 (2009).

    Article  CAS  Google Scholar 

  38. Bellingham, M. C. A review of the neural mechanisms of action and clinical efficiency of riluzole in treating amyotrophic lateral sclerosis: what have we learned in the last decade? CNS Neurosci. Ther. 17, 4–31 (2011).

    Article  CAS  Google Scholar 

  39. Lacomblez, L., Bensimon, G., Leigh, P. N., Guillet, P. & Meininger, V. Dose-ranging study of riluzole in amyotrophic lateral sclerosis. Amyotrophic Lateral Sclerosis/Riluzole Study Group II. Lancet 347, 1425–1431 (1996).

    Article  CAS  Google Scholar 

  40. Lacomblez, L. et al. Xaliproden in amyotrophic lateral sclerosis: early clinical trials. Amyotroph. Lateral Scler. Other Motor Neuron Disord. 5, 99–106 (2004).

    Article  CAS  Google Scholar 

  41. Pascuzzi, R. M. et al. A phase II trial of talampanel in subjects with amyotrophic lateral sclerosis. Amyotroph. Lateral Scler. 11, 266–271 (2010).

    Article  CAS  Google Scholar 

  42. Gordon, P. H. et al. A novel, efficient, randomized selection trial comparing combinations of drug therapy for ALS. Amyotroph. Lateral Scler. 9, 212–222 (2008).

    Article  CAS  Google Scholar 

  43. Schoenfeld, D. A. & Cudkowicz, M. Design of phase II ALS clinical trials. Amyotroph. Lateral Scler. 9, 16–23 (2008).

    Article  CAS  Google Scholar 

  44. Finkelstein, D. M., Wang, R., Ficociello, L. H. & Schoenfeld, D. A. A score test for association of a longitudinal marker and an event with missing data. Biometrics 66, 726–732 (2010).

    Article  Google Scholar 

  45. Chiò, A., Calvo, A., Moglia, C., Mazzini, L. & Mora, G. ; PARALS study group. Phenotypic heterogeneity of amyotrophic lateral sclerosis: a population based study. J. Neurol. Neurosurg. Psychiatry. 82, 740–746 (2011).

    Article  Google Scholar 

  46. Paillisse, C. et al. Prognostic factors for survival in amyotrophic lateral sclerosis patients treated with riluzole. Amyotroph. Lateral Scler. Other Motor Neuron Disord. 6, 37–44 (2005).

    Article  CAS  Google Scholar 

  47. Eisen, A. Amyotrophic lateral sclerosis—evolutionary and other perspectives. Muscle Nerve 40, 297–304 (2009).

    Article  Google Scholar 

  48. Valdmanis, P. N., Daoud, H., Dion, P. A. & Rouleau, G. A. Recent advances in the genetics of amyotrophic lateral sclerosis. Curr. Neurol. Neurosci. Rep. 9, 198–205 (2009).

    Article  CAS  Google Scholar 

  49. Turner, M. R., Kiernan, M. C., Leigh, P. N. & Talbot, K. Biomarkers in amyotrophic lateral sclerosis. Lancet Neurol. 8, 94–109 (2009).

    Article  CAS  Google Scholar 

  50. Ganesalingam, J. & Bowser, R. The application of biomarkers in clinical trials for motor neuron disease. Biomark. Med. 4, 281–297 (2010).

    Article  CAS  Google Scholar 

  51. Shefner, J. M. Statistical motor unit number estimation and ALS trials: the effect of motor unit instability. Suppl. Clin. Neurophysiol. 60, 135–141 (2009).

    Article  Google Scholar 

  52. de Carvalho, M. & Swash, M. Sensitivity of electrophysiological tests for upper and lower motor neuron dysfunction in ALS: a six-month longitudinal study. Muscle Nerve 41, 208–211 (2009).

    Google Scholar 

  53. Shefner, J. M, Cudkowicz, M. E., Zhang, H., Schoenfeld, D. & Jillapalli, D. The use of statistical MUNE in a multicenter clinical trial. Muscle Nerve 30, 463–469 (2004).

    Article  CAS  Google Scholar 

  54. Rovaris, M., Agosta, F., Pagani, E. & Filippi, M. Diffusion tensor MR imaging. Neuroimaging Clin. N. Am. 19, 37–43 (2009).

    Article  Google Scholar 

  55. Zhang, Y. et al. Progression of white matter degeneration in amyotrophic lateral sclerosis: a diffusion tensor imaging study. Amyotroph. Lateral Scler. http://dx.doi.org/10.3109/17482968.2011.593036.

  56. Turner, M. R. et al. Distinct cerebral lesions in sporadic and 'D90A' SOD1 ALS: studies with [11C] flumazenil PET. Brain 128, 1323–1329 (2005).

    Article  CAS  Google Scholar 

  57. Habert, M. O. et al. Brain perfusion imaging in amyotrophic lateral sclerosis: extent of cortical changes according to the severity and topography of motor impairment. Amyotroph. Lateral Scler. 8, 9–15 (2007).

    Article  Google Scholar 

  58. Ryberg, H. et al. Discovery and verification of amyotrophic lateral sclerosis biomarkers by proteomics. Muscle Nerve 42, 104–111 (2010).

    Article  CAS  Google Scholar 

  59. Levine, T. D., Bowser, R., Hank, N. & Saperstein, D. A pilot trial of memantine and riluzole in ALS: correlation to CSF biomarkers. Amyotroph. Lateral Scler. 11, 514–519 (2010).

    Article  CAS  Google Scholar 

  60. Yoshino, H. & Kimura, A. Investigation of the therapeutic effects of edaravone, a free radical scavenger, on amyotrophic lateral sclerosis (phase II study). Amyotroph. Lateral Scler. 7, 241–224 (2006).

    Article  CAS  Google Scholar 

  61. Cudkowicz, M. E. et al. Trial of celecoxib in amyotrophic lateral sclerosis. Ann. Neurol. 60, 22–31 (2006).

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Contributions

Both authors contributed to researching data for the article, discussion of the content, writing the article, and review and/or editing of the manuscript before submission.

Corresponding author

Correspondence to Vincent Meininger.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Gordon, P., Meininger, V. How can we improve clinical trials in amyotrophic lateral sclerosis?. Nat Rev Neurol 7, 650–654 (2011). https://doi.org/10.1038/nrneurol.2011.147

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrneurol.2011.147

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing