An MDA-supported, 10-center trial of 108 people with ALS who took the oral medication lithium carbonate — some in conjunction with the ALS drug riluzole — has found the drug does not slow ALS progression or improve survival time. The study has also shown that lithium, which is used to treat bipolar disorder, can have some concerning side effects in ALS, and when taken alone (without riluzole), may actually cause harm.
Results were announced April 13 in Toronto, at an annual meeting of the American Academy of Neurology (AAN).
Why lithium was studied
MDA initiated the lithium study after a 2008 report of a small Italian trial that found the drug slowed disease progression in ALS. The Italian study included 44 people with ALS, all of whom were taking riluzole. Of the 44, 16 also took lithium, and 28 did not.
How the study was conducted
The investigators in the current study, coordinated by neurologist Robert Miller at California Pacific Medical Center in San Francisco, used a “historical” control group trial design, meaning there was no ongoing placebo group to which participants on lithium were compared. Instead, those on lithium, or lithium plus riluzole, were compared to “historical” data on people with ALS who had received a placebo in an unrelated ALS treatment trial.
Miller, who received MDA support for this trial, is the co-director of the MDA/ALS Center at California Pacific Medical Center.
Of the 108 people in the current trial, 71 took lithium and rilzuole, 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, without riluzole, 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 (like dizziness, tremor and incoordination), compared with 88 in the control group.
Other lithium trials also were negative
Two other trials of lithium in ALS — one conducted in the United States and Canada, and the other in Italy — also failed to confirm the positive results of the first Italian study.
Negative results for the second, larger Italian trial, which involved 171 people with ALS, also were announced April 13 at the AAN meeting in Toronto. 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.
Conclusions and reflections
“My heart is heavy,” Miller said of the disappointing lithium results. “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.”
He 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.
Benefits of a trial such as this, in which the results are negative, may be hard to find for people with ALS and their families. However, the investigators have noted that it’s crucial to reveal the toxic effects of medications that have received popular support, as they have been here, so that people know to stop taking substances that can harm them.
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.
A historical control design allows all trial participants to receive the study medication, which most people prefer to do, particularly with 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.