The Effect of Diflunisal on Familial Amyloidosis

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ClinicalTrials.gov Identifier: NCT00294671

Recruitment Status : Completed

First Posted : February 22, 2006

Results First Posted : March 17, 2017

Last Update Posted : March 17, 2017

Sponsor:

Collaborators:

Food and Drug Administration (FDA)

National Institute of Neurological Disorders and Stroke (NINDS)

Information provided by (Responsible Party):

John L. Berk, Boston University

Study Description

Brief Summary:

The purpose of this study is to determine if diflunisal can prevent progressive lower leg nerve damage in patients with familial amyloidosis polyneuropathy.

Funding Source - FDA Office of Orphan Products Development (OOPD); National Institute of Neurological Disorders and Stroke (NINDS)

Condition or disease	Intervention/treatment	Phase
Familial Amyloid Polyneuropathy Familial Amyloidosis	Drug: diflunisal Other: placebo	Phase 2 Phase 3

Detailed Description:

Familial amyloidosis polyneuropathy (FAP) is a rare, lethal, autosomal dominant, neurodegenerative disease characterized by misfolding of variant transthyretin tetramer (TTR) — a transport protein produced by the liver. The disease causes TTR to become unstable, triggering amyloid fibrils to form and leading to peripheral and autonomic nerve dysfunction.

Currently, the only treatment for FAP is a liver transplant, which is expensive and risk-filled. Medicines are needed to treat this disease. Previous in vitro (in a test tube) studies have shown that a common anti-inflammatory drug called diflunisal stabilizes TTR, preventing the formation of amyloid fibrils.

The goal of this 2-year randomized, double-blind, placebo-controlled research study is to establish whether diflunisal can stop the nerve damage, or peripheral neuropathy, resulting from amyloid production in patients with FAP. Scientists already know that diflunisal prevents formation of amyloid in the test tube. This study will determine if the drug can block amyloid production in FAP patients.

Participants will be randomly chosen to receive either diflunisal or an inactive (placebo) pill twice daily for 24 months. Participants will be carefully monitored through 7 follow-up visits, either at the study center or with individual primary care physicians. Participating in the study does not preclude patients from being listed for liver transplantation.

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	130 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	Double (Participant, Investigator)
Primary Purpose:	Treatment
Official Title:	The Effect of Diflunisal on Familial Amyloidosis
Study Start Date :	February 2006
Actual Primary Completion Date :	December 2012
Actual Study Completion Date :	December 2012

Resource links provided by the National Library of Medicine

Genetics Home Reference related topics: Lattice corneal dystrophy type II Transthyretin amyloidosis

MedlinePlus related topics: Amyloidosis

Drug Information available for: Diflunisal

Genetic and Rare Diseases Information Center resources: Familial Transthyretin Amyloidosis Hereditary Amyloidosis Amyloid Neuropathy

U.S. FDA Resources

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: Diflunisal Diflunisal 250 mg po bid	Drug: diflunisal given twice daily for 24 months
Placebo Comparator: Placebo Placebo 1 po bid	Other: placebo an inactive substance given twice daily for 24 months

Outcome Measures

Primary Outcome Measures :

Neurologic Impairment Score + 7 (NIS+7) [ Time Frame: Baseline, 1 and 2 years ]
The primary endpoint, 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 neurologic deficits) to 270 points (no detectable peripheral nerve function).

Secondary Outcome Measures :

Kumamoto Neurologic Scale; [ Time Frame: Baseline, 1 and 2 years ]
Change from baseline of the Kumamoto Score (0-102 points, increasing with disease severity), a clinical neurologic scale of motor, sensory, and autonomic function combined with heart and kidney end organ measures developed to track disease progression in Familial Amyloid Polyneuropathy (ATTR-FAP)
Modified Body Mass Index (mBMI); [ Time Frame: Baseline, 1 and 2 years ]
The product of body mass index (BMI) and serum albumin level (g/L) [kg/M2xg/L].
Quality of Life Questionnaire: SF-36 Physical Component Score [ Time Frame: Baseline, 1 and 2 years ]
The 36 item short-form health survey (SF-36) was used to assess the difference between treatment groups for change of physical component scores over 2 years treatment. Range 0-100; lower scores reflect lower quality-of-life.
Quality of Life Questionnaire: SF-36 Mental Component Score [ Time Frame: Baseline, 1 and 2 years ]
The 36 item short-form health survey (SF-36) was used to assess the difference between treatment groups for change of mental component scores over 2 years treatment. Range 0-100; lower scores reflect lower quality-of-life.

Eligibility Criteria

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Ages Eligible for Study:	18 Years to 75 Years (Adult, Older Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

Age 18 to 75 years
Biopsy proven amyloidosis
Genotyping of variant transthyretin
Signs of peripheral or autonomic neuropathy

Exclusion Criteria:

Use of other non-steroidal anti-inflammatory drugs
Other causes of sensorimotor polyneuropathy
Anticipated survival <2 years or liver transplantation in <1 yr
Liver transplantation
Profound nerve, heart or kidney impairment
Pregnancy or unwillingness to use contraception by women of childbearing age
Active or recent gastrointestinal bleeding
Non-steroidal or aspirin drug allergy/hypersensitivity

Contacts and Locations

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00294671

Locations

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United States, Massachusetts
Amyloidosis Center, Boston Medical Center
Boston, Massachusetts, United States, 02118
United States, Minnesota
Mayo Clinic Rochester
Rochester, Minnesota, United States, 55905
United States, New York
Mount Sinai School of Medicine, Department of Medicine
New York, New York, United States, 10029-6574
Italy
IRCCS Policlinico San Matteo
Pavia, Italy, 27100
Japan
Kumamoto University
Kumamoto, Japan, 860-0811
Shinshu University
Matsumoto, Japan, 390-8621
Sweden
Umea University Hospital
Umea, Sweden, SE-901 86
United Kingdom
King's College Hospital
London, United Kingdom, SE5 9RS

Sponsors and Collaborators

Boston University

Food and Drug Administration (FDA)

National Institute of Neurological Disorders and Stroke (NINDS)

Investigators

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Principal Investigator:	John L. Berk, MD	Boston University

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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 S, Seldin DC, Merlini G, Skinner M, Kelly JW, Dyck PJ; Diflunisal Trial Consortium. Repurposing diflunisal for familial amyloid polyneuropathy: a randomized clinical trial. JAMA. 2013 Dec 25;310(24):2658-67. doi: 10.1001/jama.2013.283815.

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Responsible Party:	John L. Berk, Principal Investigator, Boston University
ClinicalTrials.gov Identifier:	NCT00294671 History of Changes
Other Study ID Numbers:	R01NS051306 ( U.S. NIH Grant/Contract ) FD R 002532 ( Other Grant/Funding Number: FDA Office of Orphan Products Development (OOPD) ) R01NS051306 ( U.S. NIH Grant/Contract )
First Posted:	February 22, 2006 Key Record Dates
Results First Posted:	March 17, 2017
Last Update Posted:	March 17, 2017
Last Verified:	January 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD:	No
Plan Description:	A manuscript analyzing cardiac outcomes is being prepared. We will consider IPD after the manuscript is complete and accepted.

Keywords provided by John L. Berk, Boston University:


familial amyloid polyneuropathy familial amyloidosis diflunisal amyloidosis	transthyretin peripheral neuropathy autonomic neuropathy amyloid cardiomyopathy

Additional relevant MeSH terms:

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Polyneuropathies Amyloid Neuropathies Amyloid Neuropathies, Familial Amyloidosis, Familial Amyloidosis Proteostasis Deficiencies Metabolic Diseases Peripheral Nervous System Diseases Neuromuscular Diseases Nervous System Diseases Heredodegenerative Disorders, Nervous System Neurodegenerative Diseases Genetic Diseases, Inborn	Metabolism, Inborn Errors Diflunisal Anti-Inflammatory Agents, Non-Steroidal Analgesics, Non-Narcotic Analgesics Sensory System Agents Peripheral Nervous System Agents Physiological Effects of Drugs Anti-Inflammatory Agents Antirheumatic Agents Cyclooxygenase Inhibitors Enzyme Inhibitors Molecular Mechanisms of Pharmacological Action

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