An article published Online First and in the May edition of The Lancet Neurology concludes that lithium should not be used as a treatment in patients with amyotrophic lateral sclerosis (ALS). This is contrary to promising results from a recent small pilot study that generated a high level of off-label use. According to the first double-blind randomised trial of the drug, it appears that lithium does not delay disease progression in patients ALS, also known as motor neuron disease or Lou Gehrig’s disease.
ALS is a degenerative disease of unknown cause that attacks motor neurons. It leads to progressive loss of muscle control, paralysis, and ultimately death. It affects about 30,000 Americans a year and most patients only live between three and five years after diagnosis.
Since the licensing of riluzole fifteen years ago, no new drug has been approved for the treatment of ALS. Riluzole has been shown to extend the lives of patients with ALS by an average of three months. There is currently no therapy that can cure ALS.
However, in 2008 a small pilot study reported that daily doses of the drug lithium might dramatically slow down progression of ALS. Lithium is traditionally used in the treatment of bipolar affective disorder. Results showed that after fifteen months, there were no deaths in the 16 patients treated with lithium plus riluzole. Also, 30 percent of those taking riluzole alone died. In addition, findings indicated that patients taking lithium had a slower decline in disease-related disability. Thus far, no other treatment has shown such a dramatic effect on ALS. But, the study involved only a small number of patients. Also, the participants were not blinded to treatment. Thus, definite conclusions about the effectiveness of lithium could not be made.
A team of researchers from the Northeast and Canadian ALS Consortia led by Swati Aggarwal from Massachusetts General Hospital and Lorne Zinman from Sunnybrook Health Sciences Center carried out further investigations on the potential of lithium as a possible treatment for ALS. They designed a novel, double-blind, placebo-controlled, time-to-event trial. Initially, 84 patients with ALS from across the USA and Canada were randomly assigned to receive lithium plus riluzole (40 patients) or placebo plus riluzole (44 patients) in similar doses to the pilot study. Several reviews of the data were designed; the first after the 84th person was enrolled. Then a decision was to be made on whether to expand the trial to include 250 patients.
The primary outcome measure was time to an event. This was defined as a decrease in ALS functional rating scale-revised (ALSFRS-R) score by at least six points or death. A log-rank statistical test was done at the initial interim analysis. It compared the distributions of the time to an event between the lithium and placebo groups.
After the first interim analysis, the trial was stopped as the evidence suggested that a large effect of lithium would not be seen as demonstrated in the earlier pilot study.
The authors explain: “Although a modest benefit of lithium was not ruled out by the study…we found no evidence that lithium in combination with riluzole slows progression of ALS more than riluzole alone.”
They say in closing: “At this time, there remains no convincing evidence for the use of lithium as a treatment for patients with ALS.”
In an associated note, Michael Swash from Barts and the London School of Medicine and Dentistry, London, UK, expresses approval of the unique trial design. He comments it is an important advance for testing possible future treatments for ALS because of the potential for a fast result and the option for patients to cross over from placebo to treatment.
“Safety and efficacy of lithium in combination with riluzole for treatment of amyotrophic lateral sclerosis: a randomised, double-blind, placebo-controlled trial”
Swati P Aggarwal, Lorne Zinman, Elizabeth Simpson, Jane McKinley, Katherine E Jackson, Hanika Pinto, Petra Kaufman, Robin A Conwit, David Schoenfeld, Jeremy Shefner†, Merit Cudkowicz†, and the Northeast and Canadian Amyotrophic Lateral Sclerosis consortia
DOI: 10.1016/S1474-4422(10)70068-5
Written by Stephannie Brunner (B.A.)