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Randomized Controlled Trial
. 2025 Jan;71(1):96-107.
doi: 10.1002/mus.28299. Epub 2024 Nov 17.

Estimating Meaningful Differences in Measures of Neuropathic Impairment, Health-Related Quality of Life, and Nutritional Status in Patients With Hereditary Transthyretin Amyloidosis

Folke Folkvaljon  1 , Morie Gertz  2 , Julian D Gillmore  3 , Sami Khella  4 , Ahmad Masri  5 , Mathew S Maurer  6 , Márcia Waddington Cruz  7 , Jonas Wixner  8 , Jersey Chen  9 , Barry Reicher  9 , Jesse Kwoh  10 , Aaron Yarlas  10 , John L Berk  11
Affiliations
Randomized Controlled Trial

Estimating Meaningful Differences in Measures of Neuropathic Impairment, Health-Related Quality of Life, and Nutritional Status in Patients With Hereditary Transthyretin Amyloidosis

Folke Folkvaljon et al. Muscle Nerve. 2025 Jan.

Abstract

Introduction/aims: The degree of change in neuropathic impairment and quality of life (QoL) that is clinically meaningful to patients with hereditary transthyretin amyloidosis with polyneuropathy (ATTRv-PN) is not established. This study aimed to estimate the magnitude of treatment differences that are meaningful to patients in measures of neuropathy and QoL and to determine whether eplontersen achieved a meaningful improvement versus placebo.

Methods: Data from the NEURO-TTRansform trial on patients with ATTRv-PN treated with eplontersen (n = 141) or historical placebo (n = 59) were used. Anchor-based approaches were used to estimate thresholds for meaningful differences in the modified Neuropathy Impairment Score +7 (mNIS+7) composite score, Norfolk QoL-Diabetic Neuropathy (Norfolk QoL-DN) total score, Neuropathy Symptoms and Change (NSC) total score, and modified body mass index (mBMI). Differences between the least squares means of the treatment groups were analyzed.

Results: Meaningful improvement in mNIS+7 was estimated as -4.0 points and deterioration as 1.8 points. The estimated ranges of meaningful improvement and deterioration in Norfolk QoL-DN were -12.8 to -4.0 points, and 5.9 to 14.7 points, respectively. For NSC, ranges were -2.4 to -1.3 points for meaningful improvement, and 0.6 to 5.8 points for deterioration. The estimated meaningful improvement in mBMI was 9.8 kg/m2 × g/L and deterioration was -40.9 kg/m2 × g/L. Improvements in each measure with eplontersen versus placebo were greater than the estimates of meaningful differences.

Discussion: Eplontersen demonstrated a clinically meaningful effect on neuropathic impairment, QoL, and nutritional status. Such estimates have implications for clinical practice and trials.

Keywords: anchor‐based estimates; antisense oligonucleotide; eplontersen; hereditary transthyretin amyloidosis with polyneuropathy; meaningful difference.

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Conflict of interest statement

John L. Berk has participated in ad hoc advisory committees for Alnylam, AstraZeneca, BridgeBio, Intellia, and Ionis. Folke Folkvaljon is an employee of AstraZeneca. Jersey Chen and Barry Reicher are employees of, and hold stock in, AstraZeneca. Julian D. Gillmore has acted as Advisor for Alnylam, AstraZeneca, ATTRalus, BridgeBio, Intellia, Ionis, and Pfizer. Morie Gertz reports receiving personal fees from Ionis, Alnylam, Prothena, Janssen, Sanofi, Juno, Physicians Education Resource, Johnson & Johnson, Celgene, and Research to Practice; serving on the data and safety monitoring board for AbbVie; receiving grants from Aptitude Health; receiving meeting fees from Ashfield and Sorrento; and developing educational materials for i3Health. Sami Khella reports receiving consulting fees from Ionis and Alnylam. Jesse Kwoh is an employee and stockholder of Ionis. Ahmad Masri has received research grants from Attralus, Cytokinetics, Ionis, and Pfizer; and consulting fees from Alexion, Attralus, BioMarin, Bristol Myers Squibb, Cytokinetics, Eidos, Haya, Ionis, Lexicon, Pfizer, and Tenaya. Mathew S. Maurer reports grant support from NIH R01HL139671 and R01AG081582‐01; grants and personal fees from Alnylam, Pfizer, Eidos, Prothena, and Ionis; and personal fees from AstraZeneca, Akcea, Intellia, and Novo Nordisk. Márcia Waddington Cruz is a principal investigator for the NEURO‐TTRansform trial and a consultant for Alnylam, AstraZeneca, Ionis, and Pfizer. Jonas Wixner reports receiving consulting fees from Akcea, AstraZeneca, Alnylam, Pfizer, and Intellia. Aaron Yarlas is an employee and stockholder of Ionis.

Figures

FIGURE 1
FIGURE 1
LSM difference (eplontersen minus placebo) in change from baseline, per outcome measure. Red lines indicate anchor‐based estimates of meaningful difference, with red shading demonstrating the range. Blue lines indicate distribution‐based estimates of meaningful difference. All estimates of meaningful difference are on the same side of zero because the difference between treatment versus placebo is not one of “improvement” or “deterioration,” it is a mixture of the two that reflects the clinically meaningful difference. CI, confidence interval; LSM, least squares mean; mBMI, modified body mass index; mNIS+7, modified Neuropathy Impairment Score +7; Norfolk QoL‐DN, Norfolk Quality of Life‐Diabetic Neuropathy; NSC, Neuropathy Symptoms and Change.
See this image and copyright information in PMC

References

    1. Adams D., Algalarrondo V., Polydefkis M., Sarswat N., Slama M. S., and Nativi‐Nicolau J., “Expert Opinion on Monitoring Symptomatic Hereditary Transthyretin‐Mediated Amyloidosis and Assessment of Disease Progression,” Orphanet Journal of Rare Diseases 16, no. 1 (2021): 411. - PMC - PubMed
    1. Luigetti M., Romano A., Di Paolantonio A., Bisogni G., and Sabatelli M., “Diagnosis and Treatment of Hereditary Transthyretin Amyloidosis (hATTR) Polyneuropathy: Current Perspectives on Improving Patient Care,” Therapeutics and Clinical Risk Management 16 (2020): 109–123. - PMC - PubMed
    1. Adams D., Tournev I. L., Taylor M. S., et al., “Efficacy and Safety of Vutrisiran for Patients With Hereditary Transthyretin‐Mediated Amyloidosis With Polyneuropathy: A Randomized Clinical Trial,” Amyloid 30, no. 1 (2023): 1–9. - PubMed
    1. Benson M. D., Waddington‐Cruz M., Berk J. L., et al., “Inotersen Treatment for Patients With Hereditary Transthyretin Amyloidosis,” New England Journal of Medicine 379, no. 1 (2018): 22–31. - PubMed
    1. Coelho T., W. Marques, Jr. , Dasgupta N. R., et al., “Eplontersen for Hereditary Transthyretin Amyloidosis With Polyneuropathy,” Journal of the American Medical Association 330, no. 15 (2023): 1448–1458. - PMC - PubMed

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