Discussion
muscle weakness, FAP disease, neuropathic symptoms, FAP Stage 2 vs. 15.5 points for, FAP Stage, cardiomyopathy, neuropathic progression
MUSCLE WEAKNESS, CARDIOMYOPATHY, SECONDARY, ATTRV-PN
Treatment differences on mean change and response on the NIS and NIS-LL demonstrate the efficacy of inotersen for slowing neuropathic progression in patients with ATTRv-PN. Treatment benefits of inotersen were observed for NIS and NIS-LL total and muscle weakness scores, as well as NIS sensation scores, across patient subgroups based on genetic mutation, FAP disease stage, previous treatment, cardiomyopathy status, and age of symptom onset. Responder analysis demonstrated that treatment benefits on the NIS and NIS-LL were experienced by a majority of patients with ATTRv-PN treated with inotersen (64–78%), which would indicate that treatment differences in mean changes at the group level were not due to outliers in either treatment arm. Patients treated with inotersen were significantly less likely to experience clinically meaningful progression of neuropathic symptoms, including muscle weakness and sensation, than patients who received placebo. For example, 72 and 78% of patients treated with inotersen did not experience clinically meaningful worsening on NIS and NIS-LL total scores, respectively, compared to 37 and 38% of patients who received placebo. Visual inspection of eCDF curves for change in NIS and NIS-LL total scores after 65 weeks reinforced these findings, revealing treatment differences favoring inotersen across the range of observed change scores on both measures.Treatment benefits of inotersen on the NIS-LL sensation subscale, and for both NIS and NIS-LL reflexes subscales, were observed in some, but not all, patient subgroups. For some of these subgroups where treatment differences were not statistically significant, the magnitudes of mean differences and ESs were similar to those observed in the FAS. Thus, in some of these cases, the lack of significant treatment differences could have been at least partially an effect of insufficient statistical power to detect a true treatment effect due to small sample sizes in some subgroups. Additionally, while patients treated with inotersen showed little-to-no progression on these subscales, patients who received placebo also experienced less progression on these subscales relative to the others, as shown from analyses at both the group and patient level.Patients with ATTRv-PN in FAP Stage 2 experienced the largest benefit from treatment with inotersen on the NIS and NIS-LL total scores and muscle weakness subscales. As would be expected, all NIS/NIS-LL total and domain scores are substantially worse at baseline for patients in FAP Stage 2 than for those in FAP Stage 1. Patients in FAP Stage 2 also showed the most progression in most of these measures, as evidenced by the larger increases in score compared to patients in FAP Stage 1 for the placebo arm on NIS total score (mean increase of 24.1 points for FAP Stage 2 vs. 15.5 points for FAP Stage 1, When interpreting treatment differences across subgroups, it is important to take into account the fact that these groups are not independent, but rather some of these patient characteristics covary, leading to substantial overlap in patients across some subgroups. A post hoc analysis, using χThe ability to evaluate the clinical significance of treatment differences on COA measures such as the NIS/NIS-LL is limited without the availability of RD thresholds. This study contributes interpretation guidelines for change in NIS and NIS-LL scores by providing empirically based estimates of RD thresholds that represent clinically meaningful progression of neuropathic symptoms. The RD thresholds recommended here are derived from multiple estimates, including three distribution-based estimates for all scores, and three anchor-based estimates for NIS total and sensation scores, and NIS-LL total, muscle weakness, and sensation subscale scores. The similarities in magnitudes of estimated values across the distribution-based and anchor-based estimates for scales in which both methods were used would seem to support that the distribution-based estimates for the remaining scales are similar to estimates that would be derived if appropriate anchors for those scales were available.The recommended RD thresholds for the NIS and NIS-LL total scores (8.1 and 4.7 points, respectively), are much larger than the 2-point RD threshold considered in some previous studies [This study had some limitations that should be noted. Due to the lack of suitable anchor measures for the NIS muscle weakness scores and for NIS and NIS-LL reflexes subscale scores, RD threshold estimates for these scales were derived entirely from distribution-based methods, which are typically considered to be inferior or secondary to anchor-based methods for estimating clinically meaningful change [An additional limitation of this study is that the threshold representing a meaningful change on a measure may vary as a function of a patient’s baseline severity, particularly for scales that are non-linear like those examined here [