Clinical trial NCT00294671: The Effect of Diflunisal on Familial Amyloidosis
Official title: The Effect of Diflunisal on Familial Amyloidosis
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
PHASE3
Conditions: Familial Amyloid Polyneuropathy
Familial Amyloidosis
Keywords: familial amyloid polyneuropathy
familial amyloidosis
diflunisal
amyloidosis
transthyretin
peripheral neuropathy
autonomic neuropathy
amyloid cardiomyopathy
Lead sponsor: Boston University
Sponsor class: OTHER
Collaborators: name: Food and Drug Administration (FDA)
name: National Institute of Neurological Disorders and Stroke (NINDS)
First posted: 2006-02-22
Enrollment: 130
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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)

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 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

Primary outcomes:
measure: Neurologic Impairment Score + 7 (NIS+7)
timeFrame: Baseline, 1 and 2 years
Secondary outcomes:
measure: Kumamoto Neurologic Scale;
timeFrame: Baseline, 1 and 2 years
measure: Modified Body Mass Index (mBMI);
timeFrame: Baseline, 1 and 2 years
measure: Quality of Life Questionnaire: SF-36 Physical Component Score
timeFrame: Baseline, 1 and 2 years
measure: Quality of Life Questionnaire: SF-36 Mental Component Score
timeFrame: Baseline, 1 and 2 years
Other outcomes:
Locations:
city: Boston
country: United States
facility: Amyloidosis Center, Boston Medical Center
state: Massachusetts
city: Rochester
country: United States
facility: Mayo Clinic Rochester
state: Minnesota
city: New York
country: United States
facility: Mount Sinai School of Medicine, Department of Medicine
state: New York
city: Pavia
country: Italy
facility: IRCCS Policlinico San Matteo
city: Kumamoto
country: Japan
facility: Kumamoto University
city: Matsumoto
country: Japan
facility: Shinshu University
city: Umea
country: Sweden
facility: Umea University Hospital
city: London
country: United Kingdom
facility: King's College Hospital
Study officials:
affiliation: Boston University
name: John L. Berk, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.