Background: The ALSFRS R is the primary tool for evaluating disability in clinical practice and in trials. While widely used, the scale is hampered by its ability to measure function in those with low functional status. A floor effect is observed when items reach zero and ongoing progression cannot be measured and when a person has no function on the attribute queried. The rate of ALSFRS-R decline appears to slow, and plateau in many participants, despite further deterioration.
Objectives: The Phase 3 NurOwn trial (BCT-002) enrolled patients with Advanced ALS revealing impacts of the floor effect. To further assess this effect, BCT-002 (n=189) and ProAct (n=7,712) data were evaluated to assess the presence of scale items of 0. A quantitative method (Muggeo 2003, 2008) was employed to identify a functional decline pattern reflecting a floor effect with a hinge point, demonstrating a plateau in clinical data.
Results: In both datasets, participants with lower baseline (BL) ALSFRS-R scores had the highest number of scale items of 0 at BL, which gradually declines as BL scores increase. The number of participants and magnitude of scale items reaching 0 during the treatment period increased from BL, with participants with lower BL scores most affected. In BCT-002, 100% of participants with a BL value of 24 or below had at least 1 item at 0 at BL. A similar pattern occurred in ProAct (92%). In participants with no evidence of a floor at BL (n=106), NurOwn had a higher response versus placebo (41% NurOwn, 23% placebo, p=.035), and lost less function from BL to 28 weeks (-2.68 NurOwn, -4.99 placebo, p=0.040). Results in participants with a floor effect were not statistically different.
Participants in both datasets were analytically identified as having patterns reflecting a floor effect (22.3% BCT-002, 4.7% ProAct). Scale plateau occurred around a score of 25 in ProAct and 27 BCT-002, with data after this hinge-point remaining flat.
Conclusions: A plateau in ALSFRS-R scores and scale items of 0 was observed in BCT-002 and ProAct, occurring with greatest frequency in those with Advanced ALS, who have lost so much function that further declines are not measurable. Analyses conducted on those not impacted by the floor at BL in BCT-002 reveal statistically significant, clinically meaningful treatment effects with NurOwn.
For future trials, these data suggest requiring ALSFRS-R items be at least 2 or seeking a more suitable measure for patients with advanced ALS