Lithium carbonate in amyotrophic lateral sclerosis: lack of efficacy in a dose-finding trial.
BACKGROUND
A neuroprotective effect of lithium in amyotrophic lateral sclerosis (ALS) has been recently reported. We performed a multicenter trial with lithium carbonate to assess its tolerability, safety, and efficacy in patients with ALS, comparing 2 different target blood levels (0.4-0.8 mEq/L, therapeutic group [TG], vs 0.2-0.4 mEq/L, subtherapeutic group [STG]).


METHODS
The study was a multicenter, single-blind, randomized, dose-finding trial, conducted from May 2008 to November 2009 in 21 Italian ALS centers. The trial was registered with the public database of the Italian Agency for Drugs (http://oss-sper-clin.agenziafarmaco.it/) (EudraCT number 2008-001094-15).


RESULTS
As of October 2009, a total of 171 patients had been enrolled, 87 randomized to the TG and 84 to the STG. The interim data analysis, performed per protocol, showed that 117 patients (68.4%) discontinued the study because of death/tracheotomy/severe disability, adverse events (AEs)/serious AEs (SAEs), or lack of efficacy. The Data Monitoring Committee recommended stopping the trial on November 2, 2009.


CONCLUSIONS
Lithium was not well-tolerated in this cohort of patients with ALS, even at subtherapeutic doses. The 2 doses were equivalent in terms of survival/severe disability and functional data. The relatively high frequency of AEs/SAEs and the reduced tolerability of lithium raised serious doubts about its safety in ALS.


METHODS
The study provides Class II evidence that therapeutic (0.4-0.8 mEq/L) vs subtherapeutic (0.2-0.4 mEq/L) lithium carbonate did not differ in the primary outcome of efficacy (survival/loss of autonomy) in ALS. Both target levels led to dropouts in more than 30% of participants due to patient-perceived lack of efficacy and AEs.
Chiò
A
A
Department of Neuroscience, via Cherasco 15, 10126 Torino, Italy. achio@usa.net
Borghero
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G
Calvo
A
A
Capasso
M
M
Caponnetto
C
C
Corbo
M
M
Giannini
F
F
Logroscino
G
G
Mandrioli
J
J
Marcello
N
N
Mazzini
L
L
Moglia
C
C
Monsurrò
M R
MR
Mora
G
G
Patti
F
F
Perini
M
M
Pietrini
V
V
Pisano
F
F
Pupillo
E
E
Sabatelli
M
M
Salvi
F
F
Silani
V
V
Simone
I L
IL
Sorarù
G
G
Tola
M R
MR
Volanti
P
P
Beghi
E
E
D000293:Adolescent; D000328:Adult; D000368:Aged; D000690:Amyotrophic Lateral Sclerosis / Q000097:blood / Q000188:drug therapy* / Q000401:mortality; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000097:blood / Q000627:therapeutic use*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D053208:Kaplan-Meier Estimate; D016651:Lithium Carbonate / Q000097:blood / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D016037:Single-Blind Method; D013997:Time Factors; D016896:Treatment Outcome; D055815:Young Adult
D004791:Enzyme Inhibitors; D016651:Lithium Carbonate