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Original Investigation |

Repurposing Diflunisal for Familial Amyloid Polyneuropathy:  A Randomized Clinical Trial

John L. Berk, MD1; Ole B. Suhr, MD, PhD2; Laura Obici, MD3; Yoshiki Sekijima, MD, PhD4; Steven R. Zeldenrust, MD, PhD5; Taro Yamashita, MD, PhD6; Michael A. Heneghan, MD7; Peter D. Gorevic, MD10; William J. Litchy, MD5; Janice F. Wiesman, MD1; Erik Nordh, MD, PhD2; Manuel Corato, MD, PhD8; Alessandro Lozza, MD9; Andrea Cortese, MD9; Jessica Robinson-Papp, MD10; Theodore Colton, ScD11; Denis V. Rybin, MS12; Alice B. Bisbee, MPH12; Yukio Ando, MD, PhD6; Shu-ichi Ikeda, MD, PhD4; David C. Seldin, MD, PhD1; Giampaolo Merlini, MD3; Martha Skinner, MD1; Jeffery W. Kelly, PhD13; Peter J. Dyck, MD5; for the Diflunisal Trial Consortium
[+] Author Affiliations
1Amyloidosis Center, Departments of Medicine and Neurology, Boston University School of Medicine, Boston, Massachusetts
2Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden
3Amyloidosis Research and Treatment Center, Foundation IRCCS Policlinico San Matteo and Department of Molecular Medicine, University of Pavia, Pavia, Italy
4Department of Medicine, Shinshu University School of Medicine, Matsumoto, Japan
5Departments of Medicine and Neurology, Mayo Clinic, Rochester, Minnesota
6Department of Neurology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
7Institute of Liver Studies, King’s College Hospital Foundation Trust, London, England
8Istituto Clinico Humanitas, Rozzano, Italy
9C. Mondino National Institute of Neurology, Foundation IRCCS, Pavia, Italy
10Departments of Medicine and Neurology, Mount Sinai School of Medicine, New York, New York
11Department of Epidemiology, Boston University School of Public Health, Boston, Massachusetts
12Data Coordinating Center, Boston University School of Public Health, Boston, Massachusetts
13Departments of Chemistry and Molecular and Experimental Medicine and Skaggs Institute of Chemical Biology, Scripps Research Institute, La Jolla, California
JAMA. 2013;310(24):2658-2667. doi:10.1001/jama.2013.283815.
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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 (<2-point increase in NIS+7 score; P = .007).

Conclusions and Relevance  Among patients with familial amyloid polyneuropathy, the use of diflunisal compared with placebo for 2 years reduced the rate of progression of neurological impairment and preserved quality of life. Although longer-term follow-up studies are needed, these findings suggest benefit of this treatment for familial amyloid polyneuropathy.

Trial Registration  clinicaltrials.gov Identifier: NCT00294671

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Figure.
Participant Flow

Among the 63 participants who completed study treatment, analyzable primary outcome data were obtained for 60 (placebo, n=23; diflunisal, n=37); 3 in the placebo group had inadmissible data for the Neuropathy Impairment Score plus 7 nerve tests (NIS+7). Among the 67 in whom study drug was discontinued prior to 2 years (placebo, n=40; diflunisal, n=27), 2-year primary outcome data (NIS+7) were obtained for 8 participants (placebo, n=5; diflunisal, n=3).

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