Repurposing diflunisal for familial amyloid polyneuropathy

A randomized clinical trial

John L. Berk, Ole B. Suhr, Laura Obici, Yoshiki Sekijima, Steven R. Zeldenrust, Taro Yamashita, Michael A. Heneghan, Peter D. Gorevic, William J. Litchy, Janice F. Wiesman, Erik Nordh, Manuel Corato, Alessandro Lozza, Andrea Cortese, Jessica Robinson-Papp, Theodore Colton, Denis V. Rybin, Alice B. Bisbee, Yukio Ando, Shu Ichi Ikeda & 5 others David C. Seldin, Giampaolo Merlini, Martha Skinner, Jeffery W. Kelly, Peter J. Dyck

Research output: Contribution to journalArticle

259 Citations (Scopus)

Abstract

IMPORTANCE: Familial amyloid polyneuropathy, a lethal genetic disease caused by aggregation of variant transthyretin, induces progressive peripheral nerve deficits and disability. Diflunisal, a nonsteroidal anti-inflammatory agent, stabilizes transthyretin tetramers and prevents amyloid fibril formation in vitro. OBJECTIVE: To determine the effect of diflunisal on polyneuropathy progression in patients with familial amyloid polyneuropathy. DESIGN, SETTING, AND PARTICIPANTS: International randomized, double-blind, placebo-controlled study conducted among 130 patients with familial amyloid polyneuropathy exhibiting clinically detectable peripheral or autonomic neuropathy at amyloid centers in Sweden (Umeå), Italy (Pavia), Japan (Matsumoto and Kumamoto), England (London), and the United States (Boston, Massachusetts; New York, New York; and Rochester, Minnesota) from 2006 through 2012. INTERVENTION: Participants were randomly assigned to receive diflunisal, 250 mg (n=64), or placebo (n=66) twice daily for 2 years. MAIN OUTCOMES AND MEASURES: The primary end point, the difference in polyneuropathy progression between treatments, was measured by the Neuropathy Impairment Score plus 7 nerve tests (NIS+7) which ranges from 0 (no neurological deficits) to 270 points (no detectable peripheral nerve function). Secondary outcomes included a quality-of-life questionnaire (36-Item Short-Form Health Survey [SF-36]) and modified body mass index. Because of attrition, we used likelihood-based modeling and multiple imputation analysis of baseline to 2-year data. RESULTS: By multiple imputation, the NIS+7 score increased by 25.0 (95% CI, 18.4-31.6) points in the placebo group and by 8.7 (95% CI, 3.3-14.1) points in the diflunisal group, a difference of 16.3 points (95% CI, 8.1-24.5 points; P <.001). Mean SF-36 physical scores decreased by 4.9 (95% CI, -7.6 to -2.2) points in the placebo group and increased by 1.5 (95% CI, -0.8 to 3.7) points in the diflunisal group (P <.001). Mean SF-36 mental scores declined by 1.1 (95% CI, -4.3 to 2.0) points in the placebo group while increasing by 3.7 (95% CI, 1.0-6.4) points in the diflunisal group (P = .02). By responder analysis, 29.7% of the diflunisal group and 9.4% of the placebo group exhibited neurological stability at 2 years (

Original languageEnglish
Pages (from-to)2658-2667
Number of pages10
JournalJournal of the American Medical Association
Volume310
Issue number24
DOIs
Publication statusPublished - 2013

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Familial Amyloid Neuropathies
Diflunisal
Randomized Controlled Trials
Placebos
Prealbumin
Polyneuropathies
Peripheral Nerves
Amyloid Neuropathies
Inborn Genetic Diseases
Non-Steroidal Anti-Inflammatory Agents
Health Surveys
Amyloid
Sweden
England
Italy
Japan
Body Mass Index
Quality of Life

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Berk, J. L., Suhr, O. B., Obici, L., Sekijima, Y., Zeldenrust, S. R., Yamashita, T., ... Dyck, P. J. (2013). Repurposing diflunisal for familial amyloid polyneuropathy: A randomized clinical trial. Journal of the American Medical Association, 310(24), 2658-2667. https://doi.org/10.1001/jama.2013.283815

Repurposing diflunisal for familial amyloid polyneuropathy : A randomized clinical trial. / Berk, John L.; Suhr, Ole B.; Obici, Laura; Sekijima, Yoshiki; Zeldenrust, Steven R.; Yamashita, Taro; Heneghan, Michael A.; Gorevic, Peter D.; Litchy, William J.; Wiesman, Janice F.; Nordh, Erik; Corato, Manuel; Lozza, Alessandro; Cortese, Andrea; Robinson-Papp, Jessica; Colton, Theodore; Rybin, Denis V.; Bisbee, Alice B.; Ando, Yukio; Ikeda, Shu Ichi; Seldin, David C.; Merlini, Giampaolo; Skinner, Martha; Kelly, Jeffery W.; Dyck, Peter J.

In: Journal of the American Medical Association, Vol. 310, No. 24, 2013, p. 2658-2667.

Research output: Contribution to journalArticle

Berk, JL, Suhr, OB, Obici, L, Sekijima, Y, Zeldenrust, SR, Yamashita, T, Heneghan, MA, Gorevic, PD, Litchy, WJ, Wiesman, JF, Nordh, E, Corato, M, Lozza, A, Cortese, A, Robinson-Papp, J, Colton, T, Rybin, DV, Bisbee, AB, Ando, Y, Ikeda, SI, Seldin, DC, Merlini, G, Skinner, M, Kelly, JW & Dyck, PJ 2013, 'Repurposing diflunisal for familial amyloid polyneuropathy: A randomized clinical trial', Journal of the American Medical Association, vol. 310, no. 24, pp. 2658-2667. https://doi.org/10.1001/jama.2013.283815
Berk, John L. ; Suhr, Ole B. ; Obici, Laura ; Sekijima, Yoshiki ; Zeldenrust, Steven R. ; Yamashita, Taro ; Heneghan, Michael A. ; Gorevic, Peter D. ; Litchy, William J. ; Wiesman, Janice F. ; Nordh, Erik ; Corato, Manuel ; Lozza, Alessandro ; Cortese, Andrea ; Robinson-Papp, Jessica ; Colton, Theodore ; Rybin, Denis V. ; Bisbee, Alice B. ; Ando, Yukio ; Ikeda, Shu Ichi ; Seldin, David C. ; Merlini, Giampaolo ; Skinner, Martha ; Kelly, Jeffery W. ; Dyck, Peter J. / Repurposing diflunisal for familial amyloid polyneuropathy : A randomized clinical trial. In: Journal of the American Medical Association. 2013 ; Vol. 310, No. 24. pp. 2658-2667.
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author = "Berk, {John L.} and Suhr, {Ole B.} and Laura Obici and Yoshiki Sekijima and Zeldenrust, {Steven R.} and Taro Yamashita and Heneghan, {Michael A.} and Gorevic, {Peter D.} and Litchy, {William J.} and Wiesman, {Janice F.} and Erik Nordh and Manuel Corato and Alessandro Lozza and Andrea Cortese and Jessica Robinson-Papp and Theodore Colton and Rybin, {Denis V.} and Bisbee, {Alice B.} and Yukio Ando and Ikeda, {Shu Ichi} and Seldin, {David C.} and Giampaolo Merlini and Martha Skinner and Kelly, {Jeffery W.} and Dyck, {Peter J.}",
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T1 - Repurposing diflunisal for familial amyloid polyneuropathy

T2 - A randomized clinical trial

AU - Berk, John L.

AU - Suhr, Ole B.

AU - Obici, Laura

AU - Sekijima, Yoshiki

AU - Zeldenrust, Steven R.

AU - Yamashita, Taro

AU - Heneghan, Michael A.

AU - Gorevic, Peter D.

AU - Litchy, William J.

AU - Wiesman, Janice F.

AU - Nordh, Erik

AU - Corato, Manuel

AU - Lozza, Alessandro

AU - Cortese, Andrea

AU - Robinson-Papp, Jessica

AU - Colton, Theodore

AU - Rybin, Denis V.

AU - Bisbee, Alice B.

AU - Ando, Yukio

AU - Ikeda, Shu Ichi

AU - Seldin, David C.

AU - Merlini, Giampaolo

AU - Skinner, Martha

AU - Kelly, Jeffery W.

AU - Dyck, Peter J.

PY - 2013

Y1 - 2013

N2 - IMPORTANCE: Familial amyloid polyneuropathy, a lethal genetic disease caused by aggregation of variant transthyretin, induces progressive peripheral nerve deficits and disability. Diflunisal, a nonsteroidal anti-inflammatory agent, stabilizes transthyretin tetramers and prevents amyloid fibril formation in vitro. OBJECTIVE: To determine the effect of diflunisal on polyneuropathy progression in patients with familial amyloid polyneuropathy. DESIGN, SETTING, AND PARTICIPANTS: International randomized, double-blind, placebo-controlled study conducted among 130 patients with familial amyloid polyneuropathy exhibiting clinically detectable peripheral or autonomic neuropathy at amyloid centers in Sweden (Umeå), Italy (Pavia), Japan (Matsumoto and Kumamoto), England (London), and the United States (Boston, Massachusetts; New York, New York; and Rochester, Minnesota) from 2006 through 2012. INTERVENTION: Participants were randomly assigned to receive diflunisal, 250 mg (n=64), or placebo (n=66) twice daily for 2 years. MAIN OUTCOMES AND MEASURES: The primary end point, the difference in polyneuropathy progression between treatments, was measured by the Neuropathy Impairment Score plus 7 nerve tests (NIS+7) which ranges from 0 (no neurological deficits) to 270 points (no detectable peripheral nerve function). Secondary outcomes included a quality-of-life questionnaire (36-Item Short-Form Health Survey [SF-36]) and modified body mass index. Because of attrition, we used likelihood-based modeling and multiple imputation analysis of baseline to 2-year data. RESULTS: By multiple imputation, the NIS+7 score increased by 25.0 (95% CI, 18.4-31.6) points in the placebo group and by 8.7 (95% CI, 3.3-14.1) points in the diflunisal group, a difference of 16.3 points (95% CI, 8.1-24.5 points; P <.001). Mean SF-36 physical scores decreased by 4.9 (95% CI, -7.6 to -2.2) points in the placebo group and increased by 1.5 (95% CI, -0.8 to 3.7) points in the diflunisal group (P <.001). Mean SF-36 mental scores declined by 1.1 (95% CI, -4.3 to 2.0) points in the placebo group while increasing by 3.7 (95% CI, 1.0-6.4) points in the diflunisal group (P = .02). By responder analysis, 29.7% of the diflunisal group and 9.4% of the placebo group exhibited neurological stability at 2 years (

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