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The Effect of Diflunisal on Familial Amyloidosis

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT00294671
Recruitment Status : Completed
First Posted : February 22, 2006
Results First Posted : March 17, 2017
Last Update Posted : March 17, 2017
Sponsor:
Collaborators:
Food and Drug Administration (FDA)
National Institute of Neurological Disorders and Stroke (NINDS)
Information provided by (Responsible Party):
John L. Berk, Boston University

Tracking Information
First Submitted Date  ICMJE February 21, 2006
First Posted Date  ICMJE February 22, 2006
Results First Submitted Date  ICMJE December 26, 2013
Results First Posted Date  ICMJE March 17, 2017
Last Update Posted Date March 17, 2017
Study Start Date  ICMJE February 2006
Actual Primary Completion Date December 2012   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 30, 2017)
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).
Original Primary Outcome Measures  ICMJE
 (submitted: February 21, 2006)
Neurologic Impairment Score + 7 (NIS+7) at 12 & 24 months
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: January 30, 2017)
  • 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.
Original Secondary Outcome Measures  ICMJE
 (submitted: February 21, 2006)
  • Kumamoto neurologic scale at 6, 12 & 24 months;
  • Echocardiographic signs of cardiomyopathy at 12 & 24 months;
  • Modified body mass index at 6, 12 & 24 months;
  • Amyloid burden at 12 & 24 months;
  • Quality of life questionnaire at 6, 12 & 24 months
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE The Effect of Diflunisal on Familial Amyloidosis
Official Title  ICMJE The Effect of Diflunisal on Familial Amyloidosis
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Condition  ICMJE
  • Familial Amyloid Polyneuropathy
  • Familial Amyloidosis
Intervention  ICMJE
  • Drug: diflunisal
    given twice daily for 24 months
  • Other: placebo
    an inactive substance given twice daily for 24 months
Study Arms  ICMJE
  • Active Comparator: Diflunisal
    Diflunisal 250 mg po bid
    Intervention: Drug: diflunisal
  • Placebo Comparator: Placebo
    Placebo 1 po bid
    Intervention: Other: placebo
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.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: January 30, 2017)
130
Original Enrollment  ICMJE
 (submitted: February 21, 2006)
200
Actual Study Completion Date  ICMJE December 2012
Actual Primary Completion Date December 2012   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 75 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Italy,   Japan,   Sweden,   United Kingdom,   United States
Removed Location Countries Portugal
 
Administrative Information
NCT Number  ICMJE NCT00294671
Other Study ID Numbers  ICMJE R01NS051306( U.S. NIH Grant/Contract )
FD R 002532 ( Other Grant/Funding Number: FDA Office of Orphan Products Development (OOPD) )
R01NS051306 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
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.
Responsible Party John L. Berk, Boston University
Study Sponsor  ICMJE Boston University
Collaborators  ICMJE
  • Food and Drug Administration (FDA)
  • National Institute of Neurological Disorders and Stroke (NINDS)
Investigators  ICMJE
Principal Investigator: John L. Berk, MD Boston University
PRS Account Boston University
Verification Date January 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP