Why Good Design Matters | | Merit Cudkowicz |
In 2008, after an Italian group reported a dramatic slowing of ALS progression in a small trial of patients given lithium carbonate, “the ALS community was excited,” says Swati Aggarwal, a Harvard researcher who spoke at the Packard symposium. “Our response was to design a randomized, placebo-controlled trial of lithium—the so-called gold standard.” There was urgency for more research, “both because of the magnitude of the reported effect,” adds NEALS co-chair, Merit Cudkowicz, “and because lithium is a drug with some risks. We needed to confirm if it had efficacy in ALS and if it was safe.” “The hindrance, however,” says Aggarwal, “was that patients hearing of the study began taking lithium on their own.” While that was understandable, it made it difficult to enroll them in a trial where roughly half of those participating would be on placebo and lithium-free. So she, Cudkowicz and NEALS colleagues employed an unusual “time-to-event” design. “With it, we intended to shorten the time someone would be on placebo,” says Cudkowicz, “while getting an answer quickly about lithium.” In this “time to event” trial, people continued in the trial unless—the event— their performance on a standard (ALSFRS-R) scale of ability dropped six points or death intervened. Being in the placebo group, then, wouldn’t keep anyone who might be declining rapidly from switching to the potential treatment, lithium. Also, no one in the trial would have to discontinue riluzole: it was part of the study. A third advantage was the built-in status check—a dedicated time in the midst of the trial to tell if the drug was futile as a therapy. In the end, it was this futility check that halted the study early on. “What our study did,” says Cudkowicz, “was to rule out a large effect of lithium as was reported in the Italian study.” Not incidentally, it also saved the time, expense and inconvenience of a longer, more traditional trial. The results didn’t exclude a small effect of lithium, she adds. That’s for another study with a different design. Two other trials have since reported negative results for the drug. Learn more about the lithium trial. | 
