Despite promising results from an Italian pilot study, follow-up trials of lithium in ALS have failed to show any benefits for the drug
An MDA-supported, 10-center trial of more than 100 people with amyotrophic lateral sclerosis (ALS) who took the oral medication lithium carbonate — some in conjunction with the ALS drug riluzole — has shown the drug does not provide benefit for disease progression or survival.
The study also showed that lithium can have concerning side effects, and when taken alone (without riluzole), may actually cause harm.
Results were announced April 13, 2010, in Toronto, at the annual meeting of the American Academy of Neurology (AAN).
"My heart is heavy," said study director Robert Miller, neurologist and co-director of the MDA ALS Center at California Pacific Medical Center in San Francisco. "I was more excited about this than about any other ALS trial. It shows you how very resistant this disease is and how slowly it is unlocking its secrets to us." Miller received MDA support for this trial.
Why lithium was studied
MDA began funding a lithium trial after a 2008 Italian trial of lithium in ALS showed the drug slowed disease progression. The Italian study included 44 people with ALS, all of whom were taking riluzole, a drug that slightly extends survival time in ALS. Of the 44, 16 also took lithium, and 28 did not.
How the study was conducted
The investigators in the current study used an historical control group trial design, meaning there was no ongoing placebo group to which patients on lithium were compared.
Instead, those on lithium, or lithium plus riluzole, were compared to “historical” data on participants with ALS who received placebos in a different ALS treatment trial.
In the current trial, 71 took lithium and riluzole, and they were compared with 166 historical controls, who took riluzole plus a placebo in a previous trial. A subgroup of 37 took lithium alone and were compared with 83 historical controls who took only a placebo in the previous trial.
Trial participants who took lithium plus riluzole did not live longer or progress more slowly than the historical control group that received a placebo plus riluzole. And those who took lithium alone showed faster progression than any of the other three groups.
In addition, there were significantly more (62 compared to 40) of what the U.S. Food and Drug Administration terms "serious adverse events" in people taking lithium with or without riluzole than there were in the non-lithium historical control group.
In the lithium-treated trial participants, there were 146 falls, classified as "non-serious adverse events," compared to 81 in the control group, and 123 non-serious neurological adverse events, compared with 88 in the control group.
Other lithium trials also negative
Two other trials of lithium in ALS — one conducted in the United States and Canada (see NIH ALS Lithium Trial Stops), and the other in Italy (see Italian Trial of Lithium in ALS Stopped Early) — have likewise failed to confirm the positive results of the first Italian study.
Negative results for the second, larger Italian trial involving 171 people with ALS, were originally announced in fall 2009 and were further discussed April 13 at the AAN meeting in Toronto, along with the MDA trial results. In the Italian study, a safety committee stopped the trial early after an interim analysis revealed that 117 (68 percent) of the participants had either died or dropped out of the study.
Miller said the investigators cannot fully explain why the first Italian trial showed such promising results, except that the number of people on lithium was very small — only 16 — and that the treated and untreated patients may not have been well matched on other disease-relevant characteristics.
Meaning for people with ALS
It may be hard for people with ALS and their families to find the benefits in a trial such as this, in which the results are negative. However, the investigators noted that it's crucial to reveal any toxic effects of medications, such as lithium, that at first seem to be beneficial.
The investigators also noted that the historical control design of this trial has proven itself valuable in this and other studies, and that it may be a more efficient way to conduct some ALS treatment screening trials in the future.
An historical control design allows all trial participants to receive the study medication, which most people prefer to do, particularly for an already approved drug. It also allows investigators to conduct a preliminary screening trial to decide whether to invest further resources, with fewer new participants.