Abstract
ObjectiveHereditary transthyretin amyloidosis with polyneuropathy (ATTRv-PN) is a rare disease characterized by rapid neuropathic progression. In pivotal studies of gene-silencing treatments, the modified Neuropathy Impairment Score + 7 tests (mNIS + 7) and Norfolk-Quality of Life (QOL)-Diabetic Neuropathy (DN) questionnaire assessed treatment impact on neuropathic progression. Establishing responder definition (RD) thresholds for these measures would enable evaluation of clinically meaningful treatment benefit.MethodsmNIS + 7 and Norfolk-QOL-DN were administered at baseline and week 65 to 165 adults with ATTRv-PN receiving inotersen (n = 106) or placebo (n = 59) in the NEURO-TTR study. Anchor-based approaches for estimating RD thresholds were used for Norfolk QOL-DN, while distribution-based approaches were used for both measures. Responders were patients with a score change < RD, indicating improvement or stabilization (i.e., no clinically meaningful progression). Odds ratios (ORs) and Fisher’s exact tests compared proportions of responders by treatment.ResultsThe mean RD estimates were 12.2 points and 8.8 points for mNIS + 7 and Norfolk QOL-DN, respectively. The proportions of patients whose change in score indicated improvement or stabilization were statistically significantly larger for inotersen than placebo for all estimated RD thresholds for mNIS + 7 (64–86% responders for inotersen vs. 27–46% for placebo, ORs = 3.8–7.2, ps < 0.001) and Norfolk QOL-DN (66–81% vs. 35–56%, ORs = 2.4–3.6, ps < 0.05).DiscussionEstablishing RD thresholds for these instruments enables evaluation of clinically relevant and individual-level treatment benefit on neuropathic progression. Across RDs estimated using multiple methods, a higher proportion of patients receiving inotersen than placebo showed improved or stabilized neuropathic progression at week 65.Trial registrationClinicalTrials.gov Identifier: NCT01737398; Date of registration: November 29, 2012.
Highlights
Hereditary transthyretin amyloidosis (ATTRv) is a rare, systemic, progressive, potentially fatal disease caused by mutations in the gene encoding the transthyretin (TTR) protein [1, 2]
The variability in responder definition (RD) thresholds across the different estimation statistics was fairly large for mNIS + 7, with a range of 12.1 points (6.9–19.0) and a coefficient of variation (CV) of 51%, but somewhat smaller for Norfolk Quality of Life (QOL)-Diabetic Neuropathy (DN), with a range of 7.5 points (6.4–13.8) and a CV of 29%
For distribution-based statistics, RD threshold estimates were largest for effect size (ES) and smallest for standard error of measurement (SEM) for both the mNIS + 7 and Norfolk QOL-DN
Summary
Hereditary transthyretin amyloidosis (ATTRv) is a rare, systemic, progressive, potentially fatal disease caused by mutations in the gene encoding the transthyretin (TTR) protein [1, 2]. Patients with ATTRv associated with polyneuropathy (ATTRv-PN) experience diminished health-related quality of life (HRQOL) [7,8,9], which continues to decline as the disease progresses [10, 11]. ATTRv-PN—patisiran, an RNA interference therapy, and inotersen, an antisense oligonucleotide therapy—both included mean change in the modified Neuropathy Impairment Score + 7 test (mNIS + 7), a clinician-administered assessment of neuropathic impairment, as a primary efficacy endpoint, and mean change in total score of the Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QOL-DN), a patient-reported questionnaire capturing neuropathy-related QOL, as a co-primary or key secondary efficacy endpoint [12, 13]. In the pivotal NEURO-TTR study that evaluated the safety and efficacy of 65 weeks of treatment with inotersen, mixed-effects models for repeated measures (MMRM) found statistically significant treatment benefits for inotersen, relative to placebo, on each of these measures, with placebo-corrected differences in mean changes for mNIS + 7 (− 19.7 points; 95% confidence interval [CI] − 26.4 to − 13.0; p < 0.001) and Norfolk QOL-DN total score (− 11.7 points; 95% CI − 18.3 to − 5.1; p < 0.001) [12]
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