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The Effect of Diflunisal on Familial Amyloidosis

This study has been completed.
Food and Drug Administration (FDA)
National Institute of Neurological Disorders and Stroke (NINDS)
Information provided by (Responsible Party):
John L. Berk, Boston University Identifier:
First received: February 21, 2006
Last updated: January 30, 2017
Last verified: January 2017

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 Intervention Phase
Familial Amyloid Polyneuropathy
Familial Amyloidosis
Drug: diflunisal
Other: placebo
Phase 2
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Participant, Investigator
Primary Purpose: Treatment
Official Title: The Effect of Diflunisal on Familial Amyloidosis

Resource links provided by NLM:

Further study details as provided by Boston University:

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.

Enrollment: 130
Study Start Date: February 2006
Study Completion Date: December 2012
Primary Completion Date: December 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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

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.


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

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
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its identifier: NCT00294671

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
IRCCS Policlinico San Matteo
Pavia, Italy, 27100
Kumamoto University
Kumamoto, Japan, 860-0811
Shinshu University
Matsumoto, Japan, 390-8621
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)
Principal Investigator: John L. Berk, MD Boston University
  More Information

Publications automatically indexed to this study by Identifier (NCT Number):
Responsible Party: John L. Berk, Principal Investigator, Boston University Identifier: NCT00294671     History of Changes
Other Study ID Numbers: R01NS051306 ( US NIH Grant/Contract Award Number )
FD R 002532 ( Other Grant/Funding Number: FDA Office of Orphan Products Development (OOPD) )
Study First Received: February 21, 2006
Results First Received: December 26, 2013
Last Updated: January 30, 2017
Individual Participant Data  
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 Boston University:
familial amyloid polyneuropathy
familial amyloidosis
peripheral neuropathy
autonomic neuropathy
amyloid cardiomyopathy

Additional relevant MeSH terms:
Amyloid Neuropathies
Amyloid Neuropathies, Familial
Amyloidosis, Familial
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
Anti-Inflammatory Agents, Non-Steroidal
Analgesics, Non-Narcotic
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 processed this record on May 24, 2017