The Effect of Diflunisal on Familial Amyloidosis
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)
|Familial Amyloid Polyneuropathy Familial Amyloidosis||Drug: diflunisal Other: placebo||Phase 2 Phase 3|
|Study Design:||Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
|Official Title:||The Effect of Diflunisal on Familial Amyloidosis|
- Neurologic Impairment Score + 7 (NIS+7) [ Time Frame: 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).
- Kumamoto Neurologic Scale; [ Time Frame: 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)
- Modified Body Mass Index (mBMI); [ Time Frame: 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 [ Time Frame: 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.
- Quality of Life Questionnaire: SF-36 Mental Component Score [ Time Frame: 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.
|Study Start Date:||February 2006|
|Study Completion Date:||December 2012|
|Primary Completion Date:||December 2012 (Final data collection date for primary outcome measure)|
Active Comparator: Diflunisal
Diflunisal 250 mg po bid
given twice daily for 24 months
Placebo Comparator: Placebo
Placebo 1 po bid
an inactive substance given twice daily for 24 months
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.
Please refer to this study by its ClinicalTrials.gov identifier: NCT00294671
|United States, Massachusetts|
|Amyloidosis Center, 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|
|IRCCS Policlinico San Matteo|
|Pavia, Italy, 27100|
|Kumamoto, Japan, 860-0811|
|Matsumoto, Japan, 390-8621|
|Umea University Hospital|
|Umea, Sweden, SE-901 86|
|King's College Hospital|
|London, United Kingdom, SE5 9RS|
|Principal Investigator:||John L. Berk, MD||Boston University|