Lithium trial failure raises hope for future success

By: Katie Moisse, PhD

Treating ALS patients with lithium and riluzole is no better than treating them with riluzole alone, according to a report published April 6 in Lancet Neurology. The report details the results of a highly controlled clinical trial in which both patients and researchers were blinded—meaning no one knew who was receiving lithium instead of a placebo.

The trial was a joint effort between – the Canadian ALS Clinical Trials and Research Network (CALS) and the Northeastern ALS Consortium (NEALS) - to validate the results of pilot study that showed a slowing of disease progression and an increase in survival in 16 Italian ALS patients treated with lithium and riluzole. Those results, published in 2008 in Proceedings of the National Academy of Sciences (PNAS), excited patients and clinicians alike. “We’d never seen a drug have an effect like that before—it seemed like the disease had stopped progressing,” says Lorne Zinman, MD, a neurologist at Sunnybrook Hospital in Toronto. “There was a collective gasp in the ALS community.”

But the pilot study had many limitations. The sample size was small, and the patients, who had more slowly progressing disease than average, were aware of whether they were receiving lithium or placebo. Because ALS patients all over the world were eager to start taking lithium based on the pilot study (lithium is available with a prescription), Zinman and the collaborative team of North American researchers were keen to validate the findings. “Patients and clinicians all saw this study, so it was important that we find out if [lithium really did slow disease progression] or whether it was a spurious result,” Zinman says.

Leading the collaboration, Zinman and Swati Aggarwal, MD, from Massachusetts General Hospital designed a trial that would accelerate patient recruitment by offering all patients a chance to receive the treatment, and accelerate the trial itself by measuring “time to event” (a six-point decrease on the ALS Functional Rating scale) rather than survival. “Because of this trial’s design, recruitment was very fast thanks to our altruistic, courageous patients,” Zinman says. The trial design also included a futility analysis, which would end the trial early if there was no chance for it to yield the desired effect.
While the trial’s results are disappointing, its unique design, which included provisions to allow patients in the placebo group to cross into the treatment group if their condition deteriorated, marks an a important advance in ALS treatment testing. The results also serve as a reminder that promising results from pilot studies need be carefully confirmed in appropriately designed clinical trials. “If we never did the trial, there would still be a ton of patients on lithium,” Zinman says. “Unfortunately, this is an example of another medication not panning out, but the study design should allow us to get [information on whether drugs will be effective] much more quickly now.”

The trial also established an important partnership between CALS and NEALS. “We’ve already got our next trial going,” Zinman says. “Another partnership with [the Northeast ALS Consortium] testing ceftriaxone—a cephalosporin antibiotic. We’re recruiting across Canada now.”