Impact of Crossover Treatment in Amyotrophic Lateral Sclerosis on Patient Outcomes

In patients with such fatal disorders as amyotrophic lateral sclerosis (ALS), studies that include placebo-to-active treatment crossover are encouraged, although they may underestimate the active survival benefit in these individuals. These findings were published in the journal Muscle & Nerve.

The phase 2 CENTAUR trial (ClinicalTrials.gov identifier: NCT03127514) and the CENTAUR open-label extension (CENTAUR-OLE) study (ClinicalTrials.gov identifier: NCT03488524) of a fixed-dose combination of sodium phenylbuturate (PB) and taurursodiol (TURSO) were conducted in an effort to apply methods for modeling without the use of crossover. This included the rank-preserving structural failure time model (RPSFTM). Study findings included the intent-to-treat (ITT) and RPSFTM survival analyses with final data through a cutoff date of July 2020.

The CENTAUR trial was carried out at 25 Northeast ALS Consortium centers. In this study, adults with definite ALS who were up to 18 months from symptom onset were randomized in a 2:1 ratio to receive daily PB plus TURSO or placebo by mouth or via a feeding tube. Individuals who completed the randomized phase of the trial were eligible to enroll in the OLE phase, in which they received daily PB plus TURSO for up to 40 months.

A total of 137 patients were randomized in CENTAUR (PB plus TURSO: n=89; placebo: n=48). Among 98 eligible participants, 90 continued into the OLE phase, which included 71% (34 of 48) of those participants who were originally randomized to placebo.

In the final overall survival analysis, which comprised all randomized participants at the July 2020 cutoff date, the median duration of survival was 25.8 months (95% CI,19.0 months to not reached) in the group originally randomized to PB plus TURSO vs 18.9 months (95% CI, 13.5 to 28.7 months) in the group originally randomized to placebo (difference of 6.9 months; HR, 0.57). The median duration of survival was 18.8 months longer in the PB-plus-TURSO–randomized subgroup who continued into the OLE phase vs the placebo-randomized subgroup who did not continue into the OLE phase (P <.0001).

The mean PB plus TURSO durations of exposure were 10.2 months in the group originally randomized to PB plus TURSO vs 4.6 months in the group originally randomized to placebo (all in the OLE phase).

Study findings revealed that HRs of death for participants treated with PB plus TURSO vs those initially receiving placebo were 0.57 (95% CI, 0.35 to 0.92; P =.023) in the ITT analysis and 0.39 (95% CI, 0.17 to 0.88; P =.023) for those in the primary on-treatment RPSFTM analysis.

Study limitations included the fact that the subgroups in the post hoc analysis were small. Further, potential confounding differences among the groups were not well controlled.

The researchers concluded “Such methods may provide clinical context for observed survival outcomes in future ALS crossover trials.”

Additional data from the ongoing phase 3 PHOENIX trial (ClinicalTrials.gov identifier: NCT05021536), along with clinical experience, will provide further information on the impact of PB plus TURSO on survival among individuals with ALS.

Disclosure: Some of the study authors have declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures. 

Reference  

Paganoni S, Watkins C, Cawson M, et al. Survival analyses from the CENTAUR Trial in amyotrophic lateral sclerosis: evaluating the impact of treatment crossover on outcomes. Muscle Nerve. Published online May 4, 2022. doi:10.1002/mus.27569