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ALS Treatment Trials May Require More Complex Statistical Models
The inability of placebo-to-active treatment crossover trials, involving patients with fatal conditions such as amyotrophic lateral sclerosis (ALS), to sustain a placebo group long enough to accurately assess survival may lead to an underestimation of a treatment’s effect, suggests a study published online in Muscle & Nerve.
“More complex statistical methods for modeling survival benefit in the absence of treatment crossover exist that theoretically eliminate such bias, including rank-preserving structural failure time models (RPSFTMs),” researchers wrote. “These models are used in the analysis of oncology trials, which frequently incorporate a crossover design based on ethical considerations, and are generally regarded as appropriate methods for assessing the potential effect of treatment crossover on clinical trial survival estimates.”
For the study, researchers applied methods to model survival without crossover—specifically, intent-to-treat (ITT) and RPSFTM models—to data from the CENTAUR trial of sodium phenylbutyrate and taurursodiol in patients with ALS.
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Median ITT survival duration with sodium phenylbutyrate and taurursodiol (25.8 months) was 6.9 months longer than with placebo (18.9 months) in ITT analysis and 10.6 months longer than the median RPSFTM-adjusted survival with placebo (15.2 months), researchers reported.
In the sodium phenylbutyrate and taurursodiol subgroup that continued into an open-label extension phase, median survival was 18.8 months longer than the placebo subgroup that did not continue into the open-label extension. However, open-label phase extension bias may have confounded the findings, researchers noted.
Hazard ratios of death with sodium phenylbutyrate and taurursodiol compared with placebo were 0.57 in ITT analysis and 0.39 in the RPSFTM analysis, they study showed.
“Similar to the prespecified ITT analysis, post hoc analyses adjusting for treatment crossover in CENTAUR showed a significant survival benefit for sodium phenylbutyrate and taurursodiol,” researchers wrote. “Such methods may provide clinical context for observed survival outcomes in future ALS crossover trials.”
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