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Clinical Trial
. 2011 Sep 6;77(10):973-9.
doi: 10.1212/WNL.0b013e31822dc7a5. Epub 2011 Aug 3.

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

R G Miller  1 , 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, M Ross, E P Simpson, S H Appel; WALS Study Group
Collaborators, Affiliations
Clinical Trial

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

R G Miller et al. Neurology. .

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.

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Figures

Figure 1
Figure 1. Flow chart
The disposition of subjects in the study, including the number screened, enrolled, failed, early terminated (ET), and completed. AE = adverse event.
Figure 2
Figure 2. ALS Functional Rating Scale–Revised (ALSFRS-R) slopes during the first 6 months of follow-up by study group
Study groups are the following: Western ALS Study Group (WALS) LI = WALS lithium (n = 107), Northeast ALS Consortium (NEALS) LI = NEALS lithium (n = 39), NEALS Crea = NEALS creatine placebo (n = 45), NEALS Celb = NEALS Celebrex placebo (n = 95), TCH = Novartis TCH346 assigned placebo (n = 108), WALS Mino = minocycline control (n = 249), QALS = QALS coenzyme Q10 placebo (n = 75), and NEALS Pl = NEALS lithium placebo (n = 44). Each dot represents the slope of one patient. Only patients with symptom duration ≤3 years and initial forced vital capacity ≥75% are included. Small red bar indicates median slope for the study group. Slopes are limited to the first 6 months follow-up because that was the maximum for the NEALS creatine and lithium trials. Data are listed in chronologic order.
Figure 3
Figure 3. Survival comparison
Kaplan-Meier survival curve of time to failure of lithium (red) vs placebo (blue).
See this image and copyright information in PMC

Comment in

References

    1. Miller RG, Jackson CE, Kasarskis EJ, et al. Practice parameter update: the care of the patient with amyotrophic lateral sclerosis: drug, nutritional, and respiratory therapies (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2009;73:1218–1226 - PMC - PubMed
    1. Fornai F, Longone P, Cafaro L, et al. Lithium delays progression of amyotrophic lateral sclerosis. Proc Natl Acad Sci USA 2008;105:2052–2057 - PMC - PubMed
    1. Fornai F, Longone P, Ferrucci M, et al. Autophagy and amyotrophic lateral sclerosis: the multiple roles of lithium. Autophagy 2008;4:527–530 - PubMed
    1. Sarkar S, Floto RA, Berger Z, et al. Lithium induces autophagy by inhibiting inositol monophosphatase. J Cell Biol 2005;170:1101–1111 - PMC - PubMed
    1. Sarkar S, Rubinsztein DC. Inositol and IP3 levels regulate autophagy: biology and therapeutic speculations. Autophagy 2006;2:132–134 - PubMed

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