Phase II screening trial of lithium carbonate in amyotrophic lateral sclerosis: Examining a more efficient trial design

R. G. Miller, D. H. Moore, D. A. Forshew, J. S. Katz, R. J. Barohn, M. Valan, M. B. Bromberg, K. L. Goslin, M. C. Graves, L. F. McCluskey, A. L. McVey, T. Mozaffar, J. M. Florence, A. Pestronk, Mark A Ross, E. P. Simpson, S. H. Appel

Research output: Contribution to journalArticle

51 Citations (Scopus)

Abstract

Objective: To use a historical placebo control design to determine whether lithium carbonate slows progression of amyotrophic lateral sclerosis (ALS). Methods: A phase II trial was conducted at 10 sites in the Western ALS Study Group using similar dosages (300-450 mg/day), target blood levels (0.3-0.8 mEq/L), outcome measures, and trial duration (13 months) as the positive trial. However, taking riluzole was not a requirement for study entry. Placebo outcomes in patients matched for baseline features from a large database of recent clinical trials, showing stable rates of decline over the past 9 years, were used as historical controls. Results: The mean rate of decline of the ALS Functional Rating Scale-Revised was greater in 107 patients taking lithium carbonate (-1.20/month, 95% confidence interval [CI] -1.41 to -0.98) than that in 249 control patients (-1.01/month, 95% CI -1.11 to -0.92, p = 0.04). There were no differences in secondary outcome measures (forced vital capacity, time to failure, and quality of life), but there were more adverse events in the treated group. Conclusions: The lack of therapeutic benefit and safety concerns, taken together with similar results from 2 other recent trials, weighs against the use of lithium carbonate in patients with ALS. The absence of drift over time and the availability of a large database of patients for selecting a matched historical control group suggest that use of historical controls may result in more efficient phase II trials for screening putative ALS therapeutic agents. Classification of evidence: This study provided Class IV evidence that lithium carbonate does not slow the rate of decline of function in patients with ALS over 13 months.

Original languageEnglish (US)
Pages (from-to)973-979
Number of pages7
JournalNeurology
Volume77
Issue number10
DOIs
StatePublished - Sep 6 2011
Externally publishedYes

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Lithium Carbonate
Amyotrophic Lateral Sclerosis
Placebos
Riluzole
Outcome Assessment (Health Care)
Databases
Confidence Intervals
Vital Capacity
Screening
Carbonate
Quality of Life
Clinical Trials
Safety
Control Groups
Therapeutics

ASJC Scopus subject areas

  • Clinical Neurology
  • Arts and Humanities (miscellaneous)

Cite this

Miller, R. G., Moore, D. H., Forshew, D. A., Katz, J. S., Barohn, R. J., Valan, M., ... Appel, S. H. (2011). Phase II screening trial of lithium carbonate in amyotrophic lateral sclerosis: Examining a more efficient trial design. Neurology, 77(10), 973-979. https://doi.org/10.1212/WNL.0b013e31822dc7a5

Phase II screening trial of lithium carbonate in amyotrophic lateral sclerosis : Examining a more efficient trial design. / Miller, R. G.; Moore, D. H.; Forshew, D. A.; Katz, J. S.; Barohn, R. J.; Valan, M.; Bromberg, M. B.; Goslin, K. L.; Graves, M. C.; McCluskey, L. F.; McVey, A. L.; Mozaffar, T.; Florence, J. M.; Pestronk, A.; Ross, Mark A; Simpson, E. P.; Appel, S. H.

In: Neurology, Vol. 77, No. 10, 06.09.2011, p. 973-979.

Research output: Contribution to journalArticle

Miller, RG, Moore, DH, Forshew, DA, Katz, JS, Barohn, RJ, Valan, M, Bromberg, MB, Goslin, KL, Graves, MC, McCluskey, LF, McVey, AL, Mozaffar, T, Florence, JM, Pestronk, A, Ross, MA, Simpson, EP & Appel, SH 2011, 'Phase II screening trial of lithium carbonate in amyotrophic lateral sclerosis: Examining a more efficient trial design', Neurology, vol. 77, no. 10, pp. 973-979. https://doi.org/10.1212/WNL.0b013e31822dc7a5
Miller, R. G. ; Moore, D. H. ; Forshew, D. A. ; Katz, J. S. ; Barohn, R. J. ; Valan, M. ; Bromberg, M. B. ; Goslin, K. L. ; Graves, M. C. ; McCluskey, L. F. ; McVey, A. L. ; Mozaffar, T. ; Florence, J. M. ; Pestronk, A. ; Ross, Mark A ; Simpson, E. P. ; Appel, S. H. / Phase II screening trial of lithium carbonate in amyotrophic lateral sclerosis : Examining a more efficient trial design. In: Neurology. 2011 ; Vol. 77, No. 10. pp. 973-979.
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AU - Katz, J. S.

AU - Barohn, R. J.

AU - Valan, M.

AU - Bromberg, M. B.

AU - Goslin, K. L.

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N2 - Objective: To use a historical placebo control design to determine whether lithium carbonate slows progression of amyotrophic lateral sclerosis (ALS). Methods: A phase II trial was conducted at 10 sites in the Western ALS Study Group using similar dosages (300-450 mg/day), target blood levels (0.3-0.8 mEq/L), outcome measures, and trial duration (13 months) as the positive trial. However, taking riluzole was not a requirement for study entry. Placebo outcomes in patients matched for baseline features from a large database of recent clinical trials, showing stable rates of decline over the past 9 years, were used as historical controls. Results: The mean rate of decline of the ALS Functional Rating Scale-Revised was greater in 107 patients taking lithium carbonate (-1.20/month, 95% confidence interval [CI] -1.41 to -0.98) than that in 249 control patients (-1.01/month, 95% CI -1.11 to -0.92, p = 0.04). There were no differences in secondary outcome measures (forced vital capacity, time to failure, and quality of life), but there were more adverse events in the treated group. Conclusions: The lack of therapeutic benefit and safety concerns, taken together with similar results from 2 other recent trials, weighs against the use of lithium carbonate in patients with ALS. The absence of drift over time and the availability of a large database of patients for selecting a matched historical control group suggest that use of historical controls may result in more efficient phase II trials for screening putative ALS therapeutic agents. Classification of evidence: This study provided Class IV evidence that lithium carbonate does not slow the rate of decline of function in patients with ALS over 13 months.

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