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 language | English (US) |
|---|---|
| Pages (from-to) | 973-979 |
| Number of pages | 7 |
| Journal | Neurology |
| Volume | 77 |
| Issue number | 10 |
| DOIs | |
| State | Published - Sep 6 2011 |
| Externally published | Yes |
Fingerprint
ASJC Scopus subject areas
- Clinical Neurology
- Arts and Humanities (miscellaneous)
Cite this
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 journal › Article
}
TY - JOUR
T1 - Phase II screening trial of lithium carbonate in amyotrophic lateral sclerosis
T2 - Examining a more efficient trial design
AU - Miller, R. G.
AU - Moore, D. H.
AU - Forshew, D. A.
AU - Katz, J. S.
AU - Barohn, R. J.
AU - Valan, M.
AU - Bromberg, M. B.
AU - Goslin, K. L.
AU - Graves, M. C.
AU - McCluskey, L. F.
AU - McVey, A. L.
AU - Mozaffar, T.
AU - Florence, J. M.
AU - Pestronk, A.
AU - Ross, Mark A
AU - Simpson, E. P.
AU - Appel, S. H.
PY - 2011/9/6
Y1 - 2011/9/6
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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=80055073951&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=80055073951&partnerID=8YFLogxK
U2 - 10.1212/WNL.0b013e31822dc7a5
DO - 10.1212/WNL.0b013e31822dc7a5
M3 - Article
C2 - 21813790
AN - SCOPUS:80055073951
VL - 77
SP - 973
EP - 979
JO - Neurology
JF - Neurology
SN - 0028-3878
IS - 10
ER -