The Effect of Diflunisal on Familial Amyloidosis

Boston University

Status and phase: Completed; Phase 3; Phase 2

Conditions: Familial Amyloidosis; Familial Amyloid Polyneuropathy

Treatments: Other: placebo; Drug: diflunisal

Study type: Interventional

Funder types: Other; Other U.S. Federal agency; NIH

Identifiers

NCT00294671

R01NS051306 (U.S. NIH Grant/Contract)

FD R 002532 (Other Grant/Funding Number)

Details and patient eligibility

About

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)

Full 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.

Enrollment: 130 patients

Sex: All

Ages: 18 to 75 years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Double Blind

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130 participants in 2 patient groups, including a placebo group

Diflunisal

Active Comparator group

Description:

Diflunisal 250 mg po bid

Treatment:

Drug: diflunisal

Placebo

Placebo Comparator group

Description:

Placebo 1 po bid

Treatment:

Other: placebo