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)

Study Overview

• Status: Completed
• Conditions: Familial Amyloid Polyneuropathy; Familial Amyloidosis
• Intervention / Treatment: Drug: diflunisal; Other: placebo

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.

• Study Type: Interventional
• Enrollment (Actual): 130
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Italy
  • Pavia, Italy, 27100
    • IRCCS Policlinico San Matteo
• Japan
  • Kumamoto, Japan, 860-0811
    • Kumamoto University
  • Matsumoto, Japan, 390-8621
    • Shinshu University
• Sweden
  • Umea, Sweden, SE-901 86
    • Umeå University Hospital
• United Kingdom
  • London, United Kingdom, SE5 9RS
    • King's College Hospital
• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02118
      • Amyloidosis Center, Boston Medical Center
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic Rochester
  • New York
    • New York, New York, United States, 10029-6574
      • Mount Sinai School of Medicine, Department of Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / 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

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

Collaborators and Investigators

• Sponsor: Boston University
• Collaborators: National Institute of Neurological Disorders and Stroke (NINDS); Food and Drug Administration (FDA)
• Investigators: Principal Investigator: John L. Berk, MD, Boston University

Publications and helpful links

General Publications

• Berk JL, Suhr OB, Obici L, Sekijima Y, Zeldenrust SR, Yamashita T, Heneghan MA, Gorevic PD, Litchy WJ, Wiesman JF, Nordh E, Corato M, Lozza A, Cortese A, Robinson-Papp J, Colton T, Rybin DV, Bisbee AB, Ando Y, Ikeda S, Seldin DC, Merlini G, Skinner M, Kelly JW, Dyck PJ; Diflunisal Trial Consortium. Repurposing diflunisal for familial amyloid polyneuropathy: a randomized clinical trial. JAMA. 2013 Dec 25;310(24):2658-67. doi: 10.1001/jama.2013.283815.

Study record dates

Study Major Dates

• Study Start: February 1, 2006
• Primary Completion (Actual): December 1, 2012
• Study Completion (Actual): December 1, 2012

Study Registration Dates

• First Submitted: February 21, 2006
• First Submitted That Met QC Criteria: February 21, 2006
• First Posted (Estimate): February 22, 2006

Study Record Updates

• Last Update Posted (Actual): March 17, 2017
• Last Update Submitted That Met QC Criteria: January 30, 2017
• Last Verified: January 1, 2017

More Information

Terms related to this study

• Keywords: familial amyloid polyneuropathy; familial amyloidosis; diflunisal; amyloidosis; transthyretin; peripheral neuropathy; autonomic neuropathy; amyloid cardiomyopathy
• Additional Relevant MeSH Terms: Metabolic Diseases; Nervous System Diseases; Genetic Diseases, Inborn; Neuromuscular Diseases; Neurodegenerative Diseases; Peripheral Nervous System Diseases; Proteostasis Deficiencies; Metabolism, Inborn Errors; Heredodegenerative Disorders, Nervous System; Amyloidosis; Polyneuropathies; Amyloid Neuropathies; Amyloid Neuropathies, Familial; Amyloidosis, Familial; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Cyclooxygenase Inhibitors; Diflunisal
• Other Study ID Numbers: R01NS051306 (U.S. NIH Grant/Contract); FD R 002532 (Other Grant/Funding Number: FDA Office of Orphan Products Development (OOPD))

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No
• IPD Plan Description: A manuscript analyzing cardiac outcomes is being prepared. We will consider IPD after the manuscript is complete and accepted.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No