Responder analysis for neuropathic impairment and quality-of-life assessment in patients with hereditary transthyretin amyloidosis with polyneuropathy in the NEURO-TTR study

Aaron Yarlas, Andrew Lovley, Duncan Brown, Mark Kosinski, Montserrat Vera-Llonch, Aaron Yarlas, Andrew Lovley, Duncan Brown, Mark Kosinski, Montserrat Vera-Llonch

Abstract

Objective: Hereditary 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.

Methods: mNIS + 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.

Results: The 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).

Discussion: Establishing 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 registration: ClinicalTrials.gov Identifier: NCT01737398; Date of registration: November 29, 2012.

Keywords: Clinically meaningful change; Hereditary transthyretin amyloidosis with polyneuropathy; Neuropathy; Responder analysis; Responder definition.

Conflict of interest statement

AY, AL, and MK are employees of QualityMetric, which received payment from Akcea Therapeutics, a subsidiary of Ionis Pharmaceuticals, to conduct these analyses and develop this manuscript. DB and MVL are employees of and own stock in Akcea Therapeutics, a subsidiary of Ionis Pharmaceuticals Inc.

© 2021. The Author(s).

Figures

Fig. 1
Fig. 1
Empirical distribution function curve for change in mNIS + 7 score from baseline to week 65 by treatment arm
Fig. 2
Fig. 2
Empirical distribution function curve for change in Norfolk QOL-DN total score from baseline to week 65 by treatment arm

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