Case closed for lithium treatment of ALS
medwireNews: Lithium treatment does not enhance the survival of patients with amyotrophic lateral sclerosis (ALS) despite its favorable safety profile, a study finds.
The phase III, randomized, placebo-controlled, double-blind trial found no significant increase in survival of ALS patients after 18 months of lithium treatment. The finding counters previous compelling reports of neuroprotective properties of lithium, based on cell and animal models as well as a pilot study in humans.
"[O]ur results suggest that we can now be confident that lithium at [certain] serum concentrations does not significantly influence disease progression," write Ammar Al-Chalabi (King's College, London, UK) and colleagues.
Of the 107 placebo patients, 63 (59%) were alive after 18 months of treatment of sham lithium tablets while 54 of 107 (50%) patients in the lithium group were alive after 18 months of their lithium blood concentration being kept between 0.4-0.8 mmol/L.
Neither study center and site of onset, nor treatment compliance had any effect on the hazard ratio or relative odds for survival in a manner that would indicate that lithium treatment had any influence on patient survival.
Differences between the two groups were also absent with regard to the revised ALS functional rating scale, which found a similar rate and magnitude of function loss. Similarly, anxiety and depression scores increased, while quality of life scores deteriorated to a degree that did not significantly differentiate the two groups over the course of the study.
Over half of the patients in the study had at least one serious adverse event during the 18-month follow-up period, affecting 56 placebo and 61 lithium patients. Estimated hazard ratios comparing the two treatment groups for all serious adverse events and events excluding death were nonsignificant.
"Our study was powered to detect an effect on survival but, additionally, neither standard analysis of function nor joint analysis of function and survival, which accounts for the loss of those dying with worse function, showed any benefit of lithium," writes the research team.
This finding, they conclude, underscores the importance of sufficiently powered trials that have clear endpoints when testing new treatments, which must address both the biologic underpinnings and clinical efficacy.
The greater precision and strength of this study not only questions the need for non-traditional designs of phase II trials in ALS, but also the simultaneous undertaking of several trials that investigate the same drug, write Adriano Chio and Gabriele Mora (University of Turin, Italy) in an accompanying commentary.
By Peter Sergo, medwireNews Reporter