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JAMA. 2013 Dec 25;310(24):2658-67. doi: 10.1001/jama.2013.283815.

Repurposing diflunisal for familial amyloid polyneuropathy: a randomized clinical trial.

Author information

1
Amyloidosis Center, Departments of Medicine and Neurology, Boston University School of Medicine, Boston, Massachusetts.
2
Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden.
3
Amyloidosis Research and Treatment Center, Foundation IRCCS Policlinico San Matteo and Department of Molecular Medicine, University of Pavia, Pavia, Italy.
4
Department of Medicine, Shinshu University School of Medicine, Matsumoto, Japan.
5
Departments of Medicine and Neurology, Mayo Clinic, Rochester, Minnesota.
6
Department of Neurology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
7
Institute of Liver Studies, King's College Hospital Foundation Trust, London, England.
8
Departments of Medicine and Neurology, Mount Sinai School of Medicine, New York, New York.
9
Istituto Clinico Humanitas, Rozzano, Italy.
10
C. Mondino National Institute of Neurology, Foundation IRCCS, Pavia, Italy.
11
Department of Epidemiology, Boston University School of Public Health, Boston, Massachusetts.
12
Data Coordinating Center, Boston University School of Public Health, Boston, Massachusetts.
13
Departments of Chemistry and Molecular and Experimental Medicine and Skaggs Institute of Chemical Biology, Scripps Research Institute, La Jolla, California.

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 (<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.

PMID:
24368466
PMCID:
PMC4139164
DOI:
10.1001/jama.2013.283815
[Indexed for MEDLINE]
Free PMC Article

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