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The Effect of Diflunisal on Familial Amyloidosis

Primary Purpose

Familial Amyloid Polyneuropathy, Familial Amyloidosis

Status
Completed
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
diflunisal
placebo
Sponsored by
Boston University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Familial Amyloid Polyneuropathy focused on measuring familial amyloid polyneuropathy, familial amyloidosis, diflunisal, amyloidosis, transthyretin, peripheral neuropathy, autonomic neuropathy, amyloid cardiomyopathy

Eligibility Criteria

18 Years - 75 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Amyloidosis Center, Boston Medical Center
  • Mayo Clinic Rochester
  • Mount Sinai School of Medicine, Department of Medicine
  • IRCCS Policlinico San Matteo
  • Kumamoto University
  • Shinshu University
  • Umea University Hospital
  • King's College Hospital

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Placebo Comparator

Arm Label

Diflunisal

Placebo

Arm Description

Diflunisal 250 mg po bid

Placebo 1 po bid

Outcomes

Primary Outcome Measures

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).

Secondary Outcome Measures

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)
Modified Body Mass Index (mBMI);
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
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
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.

Full Information

First Posted
February 21, 2006
Last Updated
January 30, 2017
Sponsor
Boston University
Collaborators
Food and Drug Administration (FDA), National Institute of Neurological Disorders and Stroke (NINDS)
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1. Study Identification

Unique Protocol Identification Number
NCT00294671
Brief Title
The Effect of Diflunisal on Familial Amyloidosis
Official Title
The Effect of Diflunisal on Familial Amyloidosis
Study Type
Interventional

2. Study Status

Record Verification Date
January 2017
Overall Recruitment Status
Completed
Study Start Date
February 2006 (undefined)
Primary Completion Date
December 2012 (Actual)
Study Completion Date
December 2012 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Boston University
Collaborators
Food and Drug Administration (FDA), National Institute of Neurological Disorders and Stroke (NINDS)

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Familial Amyloid Polyneuropathy, Familial Amyloidosis
Keywords
familial amyloid polyneuropathy, familial amyloidosis, diflunisal, amyloidosis, transthyretin, peripheral neuropathy, autonomic neuropathy, amyloid cardiomyopathy

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2, Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantInvestigator
Allocation
Randomized
Enrollment
130 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Diflunisal
Arm Type
Active Comparator
Arm Description
Diflunisal 250 mg po bid
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Placebo 1 po bid
Intervention Type
Drug
Intervention Name(s)
diflunisal
Intervention Description
given twice daily for 24 months
Intervention Type
Other
Intervention Name(s)
placebo
Intervention Description
an inactive substance given twice daily for 24 months
Primary Outcome Measure Information:
Title
Neurologic Impairment Score + 7 (NIS+7)
Description
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).
Time Frame
Baseline, 1 and 2 years
Secondary Outcome Measure Information:
Title
Kumamoto Neurologic Scale;
Description
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)
Time Frame
Baseline, 1 and 2 years
Title
Modified Body Mass Index (mBMI);
Description
The product of body mass index (BMI) and serum albumin level (g/L) [kg/M2xg/L].
Time Frame
Baseline, 1 and 2 years
Title
Quality of Life Questionnaire: SF-36 Physical Component Score
Description
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.
Time Frame
Baseline, 1 and 2 years
Title
Quality of Life Questionnaire: SF-36 Mental Component Score
Description
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.
Time Frame
Baseline, 1 and 2 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
75 Years
Accepts Healthy Volunteers
No
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
John L. Berk, MD
Organizational Affiliation
Boston University
Official's Role
Principal Investigator
Facility Information:
Facility Name
Amyloidosis Center, Boston Medical Center
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02118
Country
United States
Facility Name
Mayo Clinic Rochester
City
Rochester
State/Province
Minnesota
ZIP/Postal Code
55905
Country
United States
Facility Name
Mount Sinai School of Medicine, Department of Medicine
City
New York
State/Province
New York
ZIP/Postal Code
10029-6574
Country
United States
Facility Name
IRCCS Policlinico San Matteo
City
Pavia
ZIP/Postal Code
27100
Country
Italy
Facility Name
Kumamoto University
City
Kumamoto
ZIP/Postal Code
860-0811
Country
Japan
Facility Name
Shinshu University
City
Matsumoto
ZIP/Postal Code
390-8621
Country
Japan
Facility Name
Umea University Hospital
City
Umea
ZIP/Postal Code
SE-901 86
Country
Sweden
Facility Name
King's College Hospital
City
London
ZIP/Postal Code
SE5 9RS
Country
United Kingdom

12. IPD Sharing Statement

Plan to Share IPD
No
IPD Sharing Plan Description
A manuscript analyzing cardiac outcomes is being prepared. We will consider IPD after the manuscript is complete and accepted.
Citations:
PubMed Identifier
24368466
Citation
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.
Results Reference
derived

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The Effect of Diflunisal on Familial Amyloidosis

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