The Effect of Diflunisal on Familial Amyloidosis

Phase 2

Completed

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.

Recruitment & Eligibility

Inclusion Criteria

Exclusion Criteria

Arm && Interventions

Group	Intervention	Description
Placebo	placebo	Placebo 1 po bid
Diflunisal	diflunisal	Diflunisal 250 mg po bid

Primary Outcome Measures

Name	Time	Method
Neurologic Impairment Score + 7 (NIS+7)	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

Name	Time	Method
Modified Body Mass Index (mBMI);	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	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.
Kumamoto Neurologic Scale;	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)
Quality of Life Questionnaire: SF-36 Mental Component Score	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.

Locations (8): Kumamoto University
🇯🇵
Kumamoto, Japan
Mount Sinai School of Medicine, Department of Medicine
🇺🇸
New York, New York, United States
IRCCS Policlinico San Matteo
🇮🇹
Pavia, Italy
Umea University Hospital
🇸🇪
Umea, Sweden
Mayo Clinic Rochester
🇺🇸
Rochester, Minnesota, United States
King's College Hospital
🇬🇧
London, United Kingdom
Amyloidosis Center, Boston Medical Center
🇺🇸
Boston, Massachusetts, United States
Shinshu University
🇯🇵
Matsumoto, Japan