The Effect of Diflunisal on Familial Amyloidosis

Study Overview
=================
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.

Official Title
-----------------
The Effect of Diflunisal on Familial Amyloidosis

Conditions
-----------------
Familial Amyloid Polyneuropathy, Familial Amyloidosis

Intervention / Treatment
-----------------
* Drug: diflunisal
* Other: placebo


Participation Criteria
=================
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Diflunisal<br>Diflunisal 250 mg po bid | Drug: diflunisal<br>* given twice daily for 24 months<br>|
| Placebo Comparator: Placebo<br>Placebo 1 po bid | Other: placebo<br>* an inactive substance given twice daily for 24 months<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Neurologic Impairment Score + 7 (NIS+7) | 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). | Baseline, 1 and 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Kumamoto Neurologic Scale; | 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) | Baseline, 1 and 2 years | 
| Modified Body Mass Index (mBMI); | The product of body mass index (BMI) and serum albumin level (g/L) [kg/M2xg/L]. | Baseline, 1 and 2 years | 
| Quality of Life Questionnaire: SF-36 Physical Component Score | 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. | Baseline, 1 and 2 years | 
| Quality of Life Questionnaire: SF-36 Mental Component Score | 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. | Baseline, 1 and 2 years | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
familial amyloid polyneuropathy, familial amyloidosis, diflunisal, amyloidosis, transthyretin, peripheral neuropathy, autonomic neuropathy, amyloid cardiomyopathy