The Effect of Diflunisal on Familial Amyloidosis
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ClinicalTrials.gov Identifier: NCT00294671 |
Recruitment Status
:
Completed
First Posted
: February 22, 2006
Results First Posted
: March 17, 2017
Last Update Posted
: March 17, 2017
|
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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)
Condition or disease | Intervention/treatment | Phase |
---|---|---|
Familial Amyloid Polyneuropathy Familial Amyloidosis | Drug: diflunisal Other: placebo | Phase 2 Phase 3 |
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.
Study Type : | Interventional (Clinical Trial) |
Actual Enrollment : | 130 participants |
Allocation: | Randomized |
Intervention Model: | Parallel Assignment |
Masking: | Double (Participant, Investigator) |
Primary Purpose: | Treatment |
Official Title: | The Effect of Diflunisal on Familial Amyloidosis |
Study Start Date : | February 2006 |
Actual Primary Completion Date : | December 2012 |
Actual Study Completion Date : | December 2012 |

Arm | Intervention/treatment |
---|---|
Active Comparator: Diflunisal
Diflunisal 250 mg po bid
|
Drug: diflunisal
given twice daily for 24 months
|
Placebo Comparator: Placebo
Placebo 1 po bid
|
Other: placebo
an inactive substance given twice daily for 24 months
|
- 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.

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Ages Eligible for Study: | 18 Years to 75 Years (Adult, Senior) |
Sexes Eligible for Study: | All |
Accepts Healthy Volunteers: | No |
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

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): 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 | |
Italy | |
IRCCS Policlinico San Matteo | |
Pavia, Italy, 27100 | |
Japan | |
Kumamoto University | |
Kumamoto, Japan, 860-0811 | |
Shinshu University | |
Matsumoto, Japan, 390-8621 | |
Sweden | |
Umea University Hospital | |
Umea, Sweden, SE-901 86 | |
United Kingdom | |
King's College Hospital | |
London, United Kingdom, SE5 9RS |
Principal Investigator: | John L. Berk, MD | Boston University |
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: | John L. Berk, Principal Investigator, Boston University |
ClinicalTrials.gov Identifier: | NCT00294671 History of Changes |
Other Study ID Numbers: |
R01NS051306 ( U.S. NIH Grant/Contract ) FD R 002532 ( Other Grant/Funding Number: FDA Office of Orphan Products Development (OOPD) ) |
First Posted: | February 22, 2006 Key Record Dates |
Results First Posted: | March 17, 2017 |
Last Update Posted: | March 17, 2017 |
Last Verified: | January 2017 |
Individual Participant Data (IPD) Sharing Statement: | |
Plan to Share IPD: | No |
Plan Description: | A manuscript analyzing cardiac outcomes is being prepared. We will consider IPD after the manuscript is complete and accepted. |
Keywords provided by John L. Berk, Boston University:
familial amyloid polyneuropathy familial amyloidosis diflunisal amyloidosis |
transthyretin peripheral neuropathy autonomic neuropathy amyloid cardiomyopathy |
Additional relevant MeSH terms:
Amyloidosis Polyneuropathies Amyloid Neuropathies Amyloid Neuropathies, Familial Amyloidosis, Familial Proteostasis Deficiencies Metabolic Diseases Peripheral Nervous System Diseases Neuromuscular Diseases Nervous System Diseases Heredodegenerative Disorders, Nervous System Neurodegenerative Diseases Genetic Diseases, Inborn |
Metabolism, Inborn Errors Diflunisal Anti-Inflammatory Agents, Non-Steroidal Analgesics, Non-Narcotic Analgesics Sensory System Agents Peripheral Nervous System Agents Physiological Effects of Drugs Anti-Inflammatory Agents Antirheumatic Agents Cyclooxygenase Inhibitors Enzyme Inhibitors Molecular Mechanisms of Pharmacological Action |