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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

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Double (Participant, Investigator);   Primary Purpose: Treatment
Conditions Familial Amyloid Polyneuropathy
Familial Amyloidosis
Interventions Drug: diflunisal
Other: placebo
Enrollment 130
Recruitment Details Participants were recruited between May 2006 and December 2010 from amyloid centers of excellence in Sweden (Umea), Italy (Pavia), United Kingdom (London), Japan (Matsumoto and Kumamoto), and the United States (New York, Minnesota, and Massachusetts).
Pre-assignment Details All enrolled participants were randomized to treatment groups.
Arm/Group Title Diflunisal Placebo
Hide Arm/Group Description Diflunisal 250 mg taken by mouth twice daily for 24 months Placebo, an inactive substance, taken by mouth twice daily for 24 months
Period Title: Overall Study
Started 64 66
Completed 37 26
Not Completed 27 40
Reason Not Completed
Lack of Efficacy             11             23
Liver transplant             7             9
Drug related adverse event (AE)             4             2
Non-drug related AE             3             2
Lost to Follow-up             1             3
Non-compliance             1             0
Death             0             1
Arm/Group Title Diflunisal Placebo Total
Hide Arm/Group Description Diflunisal 250 mg taken by mouth twice daily for 24 months Placebo, an inactive substance, taken by mouth twice daily for 24 months Total of all reporting groups
Overall Number of Baseline Participants 64 66 130
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 64 participants 66 participants 130 participants
60.3  (11.7) 59.2  (12.2) 59.7  (11.9)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 64 participants 66 participants 130 participants
Female
21
  32.8%
22
  33.3%
43
  33.1%
Male
43
  67.2%
44
  66.7%
87
  66.9%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 64 participants 66 participants 130 participants
American Indian or Alaska Native
0
   0.0%
0
   0.0%
0
   0.0%
Asian
8
  12.5%
6
   9.1%
14
  10.8%
Native Hawaiian or Other Pacific Islander
0
   0.0%
0
   0.0%
0
   0.0%
Black or African American
1
   1.6%
5
   7.6%
6
   4.6%
White
52
  81.3%
50
  75.8%
102
  78.5%
More than one race
3
   4.7%
4
   6.1%
7
   5.4%
Unknown or Not Reported
0
   0.0%
1
   1.5%
1
   0.8%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 64 participants 66 participants 130 participants
United States 34 35 69
United Kingdom 3 4 7
Italy 10 11 21
Japan 5 4 9
Sweden 12 12 24
NIS+7 score   [1] 
Mean (Standard Deviation)
Unit of measure:  Units on a scale
Number Analyzed 64 participants 66 participants 130 participants
51.6  (42.8) 59.0  (50) 55.3  (46.5)
[1]
Measure Description: Higher scores indicating greater neurologic deficits (0=no neurologic impairment, 270=no detectable peripheral neurologic function)
Kumamoto score   [1] 
Mean (Standard Deviation)
Unit of measure:  Units on a scale
Number Analyzed 64 participants 66 participants 130 participants
15.3  (10.8) 16.7  (13.5) 16.0  (12.2)
[1]
Measure Description: Higher scores indicating greater neurologic and end organ deficits (0=no neurologic deficits, 102=no detectable peripheral neurologic function)
Modified BMI   [1] 
Mean (Standard Deviation)
Unit of measure:  kg/M2 x g/L
Number Analyzed 64 participants 66 participants 130 participants
1024.4  (226.3) 1019  (255) 1021.7  (240.4)
[1]
Measure Description: The product of BMI and serum albumin (g/L). Lower scores indicate worse nutritional status.
SF-36 physical component score   [1] 
Mean (Standard Deviation)
Unit of measure:  Units on a scale
Number Analyzed 64 participants 66 participants 130 participants
35.9  (11.6) 34.8  (11) 35.4  (11.3)
[1]
Measure Description: Higher scores indicate greater physical quality of life, scale from 0 to 100 points
SF-36 mental component score   [1] 
Mean (Standard Deviation)
Unit of measure:  Units on a scale
Number Analyzed 64 participants 66 participants 130 participants
46.6  (14.1) 46.5  (11.8) 46.6  (12.9)
[1]
Measure Description: Higher scores indicate greater mental quality of life, scale 0-100 points
1.Primary Outcome
Title Neurologic Impairment Score + 7 (NIS+7)
Hide 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
Hide Outcome Measure Data
Hide Analysis Population Description
Longitudinal analysis examined data from all 130 participants using intention-to-treat principles.
Arm/Group Title Diflunisal Placebo
Hide Arm/Group Description:
Diflunisal 250 mg taken by mouth twice daily for 24 months
Placebo, an inactive substance, taken by mouth twice daily for 24 months
Overall Number of Participants Analyzed 64 66
Mean (95% Confidence Interval)
Unit of Measure: units on a scale
Change from baseline to 2 years
8.2
(2.9 to 13.6)
26.3
(20.2 to 32.4)
Change from baseline to 1 year
6.2
(2.8 to 9.6)
12.5
(8.6 to 16.4)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Diflunisal, Placebo
Comments Longitudinal analysis of the difference between placebo and diflunisal treatment groups in NIS+7 change from baseline to 2 years.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method t-test, 2 sided
Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Diflunisal, Placebo
Comments Longitudinal analysis of the difference between placebo and diflunisal treatment groups in NIS+7 change from baseline to 1years.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.02
Comments [Not Specified]
Method t-test, 2 sided
Comments [Not Specified]
2.Secondary Outcome
Title Kumamoto Neurologic Scale;
Hide 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
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Diflunisal Placebo
Hide Arm/Group Description:
Diflunisal 250 mg taken by mouth twice daily for 24 months
Placebo, an inactive substance, taken by mouth twice daily for 24 months
Overall Number of Participants Analyzed 64 66
Mean (95% Confidence Interval)
Unit of Measure: units on a scale
Change from baseline to 2 years
3.1
(1.1 to 5.1)
8.0
(5.8 to 10.3)
Change from baseline to 1 year
1.9
(0.1 to 3.7)
4.1
(2.1 to 6.2)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Diflunisal, Placebo
Comments Longitudinal analysis of the difference between placebo and diflunisal treatment groups in Kumamoto score change from baseline to 2 years.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.002
Comments [Not Specified]
Method t-test, 2 sided
Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Diflunisal, Placebo
Comments Longitudinal analysis of the difference between placebo and diflunisal treatment groups in Kumamoto score change from baseline to 1 year.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.10
Comments [Not Specified]
Method t-test, 2 sided
Comments [Not Specified]
3.Secondary Outcome
Title Modified Body Mass Index (mBMI);
Hide Description The product of body mass index (BMI) and serum albumin level (g/L) [kg/M2xg/L].
Time Frame Baseline, 1 and 2 years
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Diflunisal Placebo
Hide Arm/Group Description:
Diflunisal 250 mg taken by mouth twice daily for 24 months
Placebo, an inactive substance, taken by mouth twice daily for 24 months
Overall Number of Participants Analyzed 64 66
Mean (95% Confidence Interval)
Unit of Measure: kg/M2xg/L
Change from baseline to 2 years
-33.7
(-69.3 to 1.8)
-67.9
(-108.1 to -27.7)
Change from baseline to 1 year
-18.7
(-51.6 to 14.1)
-38.5
(-74.9 to -2.1)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Diflunisal, Placebo
Comments Longitudinal analysis of the difference between placebo and diflunisal treatment groups in mBMI change from baseline to 2 years.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.21
Comments [Not Specified]
Method t-test, 2 sided
Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Diflunisal, Placebo
Comments Longitudinal analysis of the difference between placebo and diflunisal treatment groups in mBMI change from baseline to 1 year.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.43
Comments [Not Specified]
Method t-test, 2 sided
Comments [Not Specified]
4.Secondary Outcome
Title Quality of Life Questionnaire: SF-36 Physical Component Score
Hide 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
Hide Outcome Measure Data
Hide Analysis Population Description
Longitudinal analysis examined data from all 130 participants using intention-to-treat principles.
Arm/Group Title Diflunisal Placebo
Hide Arm/Group Description:
Diflunisal 250 mg taken by mouth twice daily for 24 months
Placebo, an inactive substance, taken by mouth twice daily for 24 months
Overall Number of Participants Analyzed 64 66
Mean (95% Confidence Interval)
Unit of Measure: units on a scale
Change from baseline to 2 years
1.2
(-1.2 to 3.7)
-4.9
(-7.6 to -2.1)
Change from baseline to 1 year
0.7
(-1.1 to 2.5)
-1.9
(-3.9 to 0.2)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Diflunisal, Placebo
Comments Longitudinal analysis of the difference between placebo and diflunisal treatment groups in SF-36 physical component change from baseline to 2 years.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.001
Comments [Not Specified]
Method t-test, 2 sided
Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Diflunisal, Placebo
Comments Longitudinal analysis of the difference between placebo and diflunisal treatment groups in SF-36 physical component change from baseline to 1 year.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.06
Comments [Not Specified]
Method t-test, 2 sided
Comments [Not Specified]
5.Secondary Outcome
Title Quality of Life Questionnaire: SF-36 Mental Component Score
Hide 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
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Diflunisal Placebo
Hide Arm/Group Description:
Diflunisal 250 mg taken by mouth twice daily for 24 months
Placebo, an inactive substance, taken by mouth twice daily for 24 months
Overall Number of Participants Analyzed 64 66
Mean (95% Confidence Interval)
Unit of Measure: units on a scale
Change from baseline to 2 years
3.5
(0.4 to 6.7)
-0.9
(-4.4 to 2.5)
Change from baseline to 1 year
2.5
(0.0 to 5.1)
0.8
(-2.0 to 3.6)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Diflunisal, Placebo
Comments Longitudinal analysis of the difference between placebo and diflunisal treatment groups in SF-36 mental component change from baseline to 2 years.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.06
Comments [Not Specified]
Method t-test, 2 sided
Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Diflunisal, Placebo
Comments Longitudinal analysis of the difference between placebo and diflunisal treatment groups in SF-36 mental component change from baseline to 1 year.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.37
Comments [Not Specified]
Method t-test, 2 sided
Comments [Not Specified]
Time Frame Adverse event data were collected for 2 years or until study withdrawal.
Adverse Event Reporting Description Adverse events were collected and analyzed by affected organ system.
 
Arm/Group Title Diflunisal Placebo
Hide Arm/Group Description Diflunisal 250 mg taken by mouth twice daily for 24 months Placebo, an inactive substance, taken by mouth twice daily for 24 months
All-Cause Mortality
Diflunisal Placebo
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--      --/--    
Hide Serious Adverse Events
Diflunisal Placebo
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   3/64 (4.69%)      4/66 (6.06%)    
Cardiac disorders     
Cardiac disorders  1  2/64 (3.13%)  2 1/66 (1.52%)  2
Gastrointestinal disorders     
Gastrointestinal disorders  1  1/64 (1.56%)  3 2/66 (3.03%)  3
Infections and infestations     
Infections and infestations  1  0/64 (0.00%)  0 1/66 (1.52%)  1
Injury, poisoning and procedural complications     
Injury, poisoning and procedural complications  1  1/64 (1.56%)  1 0/66 (0.00%)  0
Renal and urinary disorders     
Renal and urinary disorders  1  0/64 (0.00%)  0 2/66 (3.03%)  2
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 15.1
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
Diflunisal Placebo
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   29/64 (45.31%)      27/66 (40.91%)    
Blood and lymphatic system disorders     
Blood and lymphatic system disorders  1  1/64 (1.56%)  3/66 (4.55%) 
Cardiac disorders     
Cardiac disorders  1  15/64 (23.44%)  9/66 (13.64%) 
Ear and labyrinth disorders     
Ear and labyrinth disorders  1  1/64 (1.56%)  1/66 (1.52%) 
Endocrine disorders     
Endocrine disorders  1  1/64 (1.56%)  0/66 (0.00%) 
Eye disorders     
Eye disorders  1  8/64 (12.50%)  9/66 (13.64%) 
Gastrointestinal disorders     
GI disorders  1  23/64 (35.94%)  25/66 (37.88%) 
General disorders     
General disorders  1  19/64 (29.69%)  7/66 (10.61%) 
Hepatobiliary disorders     
Hepatobiliary disorders  1  1/64 (1.56%)  0/66 (0.00%) 
Immune system disorders     
Immune system disorders  1  1/64 (1.56%)  0/66 (0.00%) 
Infections and infestations     
Infections  1  24/64 (37.50%)  27/66 (40.91%) 
Injury, poisoning and procedural complications     
Injury, poisoning and procedural complications  1  13/64 (20.31%)  9/66 (13.64%) 
Investigations     
Investigations  1  11/64 (17.19%)  11/66 (16.67%) 
Metabolism and nutrition disorders     
Metabolism and nutrition disorders  1  4/64 (6.25%)  9/66 (13.64%) 
Musculoskeletal and connective tissue disorders     
Musculoskeletal and connective tissue disorders  1  19/64 (29.69%)  8/66 (12.12%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
Neoplasms  1  2/64 (3.13%)  1/66 (1.52%) 
Nervous system disorders     
Nervous system disorders  1  23/64 (35.94%)  20/66 (30.30%) 
Psychiatric disorders     
Psychiatric disorders  1  5/64 (7.81%)  7/66 (10.61%) 
Renal and urinary disorders     
Renal and urinary disorders  1  10/64 (15.63%)  12/66 (18.18%) 
Reproductive system and breast disorders     
Reproductive system and breast disorders  1  1/64 (1.56%)  0/66 (0.00%) 
Respiratory, thoracic and mediastinal disorders     
Respiratory disorders  1  12/64 (18.75%)  11/66 (16.67%) 
Skin and subcutaneous tissue disorders     
Skin and subcutaneous tissue disorders  1  6/64 (9.38%)  6/66 (9.09%) 
Surgical and medical procedures     
Surgical and medical procedures  1  5/64 (7.81%)  3/66 (4.55%) 
Vascular disorders     
Vascular disorders  1  11/64 (17.19%)  7/66 (10.61%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 15.1
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Dr. John L. Berk
Organization: Amyloidosis Center, Boston Medical Center
Phone: 617-638-4494
EMail: jberk@bu.edu
Layout table for additonal information
Responsible Party: John L. Berk, Boston University
ClinicalTrials.gov Identifier: NCT00294671    
Other Study ID Numbers: 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 )
First Submitted: February 21, 2006
First Posted: February 22, 2006
Results First Submitted: December 26, 2013
Results First Posted: March 17, 2017
Last Update Posted: March 17, 2017