The Effect of Diflunisal on Familial Amyloidosis - Full Text View

Purpose

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 OOPD; NINDS

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


Study Type:	Interventional
Study Design:	Allocation: Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Parallel Assignment Masking: Double Blind (Subject, Investigator) Primary Purpose: Treatment
Official Title:	The Effect of Diflunisal on Familial Amyloidosis

Resource links provided by NLM:

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 Amyloid Neuropathy Hereditary Amyloidosis

U.S. FDA Resources

Further study details as provided by Boston University:

Primary Outcome Measures:

Neurologic Impairment Score + 7 (NIS+7) [ Time Frame: at 12 & 24 months ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

Kumamoto neurologic scale; [ Time Frame: at 6, 12 & 24 months ] [ Designated as safety issue: No ]
Echocardiographic signs of cardiomyopathy; [ Time Frame: at 12 & 24 months ] [ Designated as safety issue: No ]
Modified body mass index ; [ Time Frame: at 6, 12 & 24 months ] [ Designated as safety issue: No ]
Amyloid burden ; [ Time Frame: at 12 & 24 months ] [ Designated as safety issue: No ]
Quality of life questionnaire [ Time Frame: at 6, 12 & 24 months ] [ Designated as safety issue: No ]


Enrollment:	140
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: 1 diflunisal	Drug: diflunisal given twice daily for 24 months
Placebo Comparator: 2 placebo	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.

Eligibility


Ages Eligible for Study:	18 Years to 75 Years (Adult, Senior)
Genders Eligible for Study:	Both
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

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 ClinicalTrials.gov identifier: NCT00294671

Locations


United States, Massachusetts
Amyloid Treatment and Research Program, 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


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.


Responsible Party:	John L. Berk, Principal Investigator, Boston University
ClinicalTrials.gov Identifier:	NCT00294671 History of Changes
Other Study ID Numbers:	R01NS051306 FD R 002532
Study First Received:	February 21, 2006
Last Updated:	May 12, 2013
Health Authority:	United States: Food and Drug Administration

Keywords provided by Boston University:


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

Additional relevant MeSH terms:


Amyloidosis Polyneuropathies 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 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

ClinicalTrials.gov processed this record on September 30, 2016