title: Repurposing diflunisal for familial amyloid polyneuropathy: a randomized clinical trial.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  METHODS
  Participants were randomly assigned to receive diflunisal, 250 mg (n=64), or placebo (n=66) twice daily for 2 years.
  
  
  METHODS
  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
  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.
  
  
  BACKGROUND
  clinicaltrials.gov Identifier: NCT00294671.
authors.affiliation: Amyloidosis Center, Departments of Medicine and Neurology, Boston University School of Medicine, Boston, Massachusetts.
authors.forename: John L
authors.initials: JL
authors.lastname: Berk
authors.affiliation: Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden.
authors.forename: Ole B
authors.initials: OB
authors.lastname: Suhr
authors.affiliation: Amyloidosis Research and Treatment Center, Foundation IRCCS Policlinico San Matteo and Department of Molecular Medicine, University of Pavia, Pavia, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Obici
authors.affiliation: Department of Medicine, Shinshu University School of Medicine, Matsumoto, Japan.
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Sekijima
authors.affiliation: Departments of Medicine and Neurology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Steven R
authors.initials: SR
authors.lastname: Zeldenrust
authors.affiliation: Department of Neurology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Taro
authors.initials: T
authors.lastname: Yamashita
authors.affiliation: Institute of Liver Studies, King's College Hospital Foundation Trust, London, England.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Heneghan
authors.affiliation: Departments of Medicine and Neurology, Mount Sinai School of Medicine, New York, New York.
authors.forename: Peter D
authors.initials: PD
authors.lastname: Gorevic
authors.affiliation: Departments of Medicine and Neurology, Mayo Clinic, Rochester, Minnesota.
authors.forename: William J
authors.initials: WJ
authors.lastname: Litchy
authors.affiliation: Amyloidosis Center, Departments of Medicine and Neurology, Boston University School of Medicine, Boston, Massachusetts.
authors.forename: Janice F
authors.initials: JF
authors.lastname: Wiesman
authors.affiliation: Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden.
authors.forename: Erik
authors.initials: E
authors.lastname: Nordh
authors.affiliation: Istituto Clinico Humanitas, Rozzano, Italy.
authors.forename: Manuel
authors.initials: M
authors.lastname: Corato
authors.affiliation: C. Mondino National Institute of Neurology, Foundation IRCCS, Pavia, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Lozza
authors.affiliation: C. Mondino National Institute of Neurology, Foundation IRCCS, Pavia, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Cortese
authors.affiliation: Departments of Medicine and Neurology, Mount Sinai School of Medicine, New York, New York.
authors.forename: Jessica
authors.initials: J
authors.lastname: Robinson-Papp
authors.affiliation: Department of Epidemiology, Boston University School of Public Health, Boston, Massachusetts.
authors.forename: Theodore
authors.initials: T
authors.lastname: Colton
authors.affiliation: Data Coordinating Center, Boston University School of Public Health, Boston, Massachusetts.
authors.forename: Denis V
authors.initials: DV
authors.lastname: Rybin
authors.affiliation: Data Coordinating Center, Boston University School of Public Health, Boston, Massachusetts.
authors.forename: Alice B
authors.initials: AB
authors.lastname: Bisbee
authors.affiliation: Department of Neurology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Yukio
authors.initials: Y
authors.lastname: Ando
authors.affiliation: Department of Medicine, Shinshu University School of Medicine, Matsumoto, Japan.
authors.forename: Shu-ichi
authors.initials: S
authors.lastname: Ikeda
authors.affiliation: Amyloidosis Center, Departments of Medicine and Neurology, Boston University School of Medicine, Boston, Massachusetts.
authors.forename: David C
authors.initials: DC
authors.lastname: Seldin
authors.affiliation: Amyloidosis Research and Treatment Center, Foundation IRCCS Policlinico San Matteo and Department of Molecular Medicine, University of Pavia, Pavia, Italy.
authors.forename: Giampaolo
authors.initials: G
authors.lastname: Merlini
authors.affiliation: Amyloidosis Center, Departments of Medicine and Neurology, Boston University School of Medicine, Boston, Massachusetts.
authors.forename: Martha
authors.initials: M
authors.lastname: Skinner
authors.affiliation: Departments of Chemistry and Molecular and Experimental Medicine and Skaggs Institute of Chemical Biology, Scripps Research Institute, La Jolla, California.
authors.forename: Jeffery W
authors.initials: JW
authors.lastname: Kelly
authors.affiliation: Departments of Medicine and Neurology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Dyck
mesh_terms: D000368:Aged; D028227:Amyloid Neuropathies, Familial / Q000188:drug therapy* / Q000503:physiopathology; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D015992:Body Mass Index; D004061:Diflunisal / Q000627:therapeutic use*; D018450:Disease Progression; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D011788:Quality of Life; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D004061:Diflunisal