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Two independent futility studies that set out to confirm that lithium slows the progression of amyotrophic lateral sclerosis (ALS) — a finding by a team of Italian investigators in 2008 that sent thousands of patients to their doctors demanding a prescription — reported that it didn't work.

The trials — one led by Robert G. Miller, MD, director of the Forbes Norris MDA/ALS Research Center at California Pacific Medical Center in San Francisco, and carried out at ten sites around the country, and another at Massachusetts General Hospital led by Swati P. Aggarwal, MD, which was reported online on April 6 in the Lancet Neurology — were both futility studies — though with different designs.

The investigators, who reported their findings at the AAN annual meeting in Toronto last month, pointed to the use of futility designs as a means to more quickly and efficiently assess novel treatments in ALS — and a sign of things to come.

Phase III studies for neurodegenerative disorders generally require hundreds of patients to be followed for at least two to three years at a high cost, the investigators said, a difficult requirement for a condition like ALS. Futility designs enable investigators to weed out agents at the preliminary study stage while requiring far fewer patients and resources, they said.

Dr. Miller said that many ALS investigators worried about the power of the Italian study — reported by Francesco Fornai, MD, PhD, and colleagues at the University of Pisa in the February 2008 Proceedings of the National Academy of Sciences - to show such a dramatic benefit of lithium. Dr. Fornai had reported that 16 patients who took lithium plus riluzole for 15 months had not progressed on the revised ALS functional rating scale, and that patients taking only riluzole continued to get sicker.

“When you go for 15 months and see no untoward events, no severe progression, it becomes a questionable assessment,” Dr. Appel said. “Many of us were concerned about the structure of the Italian study.”

Dr. Miller's Western ALS Study Group was hoping to see any kind of benefit and compared any changes among 108 ALS patients against a group of historical controls — 249 ALS patients who had been on a placebo dose as part of the federally funded trial of minocycline. The investigators finished out the year, but in the end, there was no benefit to patients taking lithium.

At the same time, the Mass General investigators of the Northeast and Canadian Amyotrophic Lateral Sclerosis Consortia designed a double blind placebo control design with 84 patients with a time-to-event design. Between January and June 2009, patients with ALS who were taking a stable dose of riluzole for at least 30 days were randomly assigned to receive lithium or placebo.

The primary endpoint was the time to an event, defined as a decrease of at least six points on the revised ALS functional rating scale score or death, and interim analyses were planned for when 84 patients had received treatment, six months later or after 55 100 events. The stopping boundary for futility at the first interim analysis was a p value of at least 0.68.

With the futility design, the differences on the rating scale amounted to a 40 percent difference between the two treatment groups. They also found no differences when they compared the 40 patients on lithium (and riluzole) to the 44 controls who were just taking riluzole. At the first interim analysis, they found 22 of 40 patients on lithium had an event measured by the severe drop on the rating scale or death compared with 20 of 44 patients in the placebo group.

The study was stopped at the first interim analysis — at six months — because the criterion for futility was met. “It was clear that lithium was just not working to improve life for ALS patients,” said Mass General's Dr. Aggarwal.

The time-to-event endpoint and use of prespecified interim analyses enabled a clear result to be obtained rapidly, Dr. Aggarwal said, “This design should be considered for future trials testing the therapeutic efficacy of drugs that are easily accessible to people with ALS.”

So what went wrong in the Italian study? Dr. Miller thinks that the study group was too small — 16 patients on lithium — and patients in both groups were not well matched. ALS patients may have an average life expectancy of five years but some die in six months and others can live well beyond a decade. With a large group of study patients the mismatching of such designs balance out. “But if you treat a slowly changing group with an experimental drug it can look like a great drug,” Dr. Miller said.

If there is a silver lining, Dr. Miller said, it is that the use of historical control groups may well set the tone for future trials. These historical controls — placebo patients — can actually help expedite a study and provide an answer to patients with no time to spare, Dr. Miller said.

He said that many of the failed studies in double-blind, placebo-controlled trials have led many ALS patients to decline participation.

The Western ALS Study Group doctors calculated that it would take 100 patients and no more than a year to show whether lithium would benefit patients. They conducted three interim analyses for safety and found no reason to stop prematurely, and they continued for the full year just in case there were small beneficial effects that weren't immediately noticeable.•


• Aggarwal SP, Zinman L, Cudkowicz M, et al, for the Northeast and Canadian Amyotrophic Lateral Sclerosis Consortia. Safety and efficacy of lithium in combination with riluzole for treatment of amyotrophic lateral sclerosis: A randomized double-blind, placebo-controlled trial. Lancet Neurol 2010; E-pub 2010 Apr 6.
    • Fornai F, Longone P, Cafaro L, et al. Lithium delays progression of amyotrophic lateral sclerosis. Proc Natl Acad Sci USA 2008;105:2052–2057.
      • Czaplinski A, Haverkamp LJ, Appel SH, et al. The value of database controls in pilot or futility studies in ALS. Neurology 2006: 67:1827–1832.