CompletedNCT00294671Updated Mar 17, 2017Results posted

The Effect of Diflunisal on Familial Amyloidosis

A Phase 2/3 interventional study of diflunisal and placebo in Familial Amyloid Polyneuropathy and Familial Amyloidosis, sponsored by Boston University. Completed at 8 sites in 5 countries. Open to participants aged 18 Years to 75 Years. Per ClinicalTrials.gov, last updated 2017-03-17.

Sponsored by Boston University · Phase 2/3, Interventional, and Treatment

Phase: Phase 2/3
Study type: Interventional
Enrollment: 130
Allocation: Randomized
Ages: 18 Years to 75 Years
Sex: All

Study 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)

Read the 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.

Conditions studied

Familial Amyloid Polyneuropathy
Familial Amyloidosis

Browse trials for

Keywords

familial amyloid polyneuropathy
familial amyloidosis
diflunisal
amyloidosis
transthyretin
peripheral neuropathy
autonomic neuropathy
amyloid cardiomyopathy

In context

Polyneuropathies

256 studies on the registry are indexed under Polyneuropathies; 50 are open to participants now.

This study's enrollment of 130 is above the median of 75 across 162 interventional studies indexed under Polyneuropathies.

Browse Polyneuropathies studies →

Lead sponsor

Boston University is the lead sponsor of 266 studies on the registry; 37 are open to participants now.

Of its 30 completed or terminated interventional studies of FDA-regulated products, 24 (80%) have results posted.

Counted across the registry records on this site, refreshed daily.

Who can participate

Ages eligible: 18 Years to 75 Years
Sexes eligible: 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

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 design

Phase: Phase 2 / Phase 3
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel assignment
Masking: Double (Participant, Investigator)
Enrollment: 130 participants (actual)

Study arms

Active comparator
Diflunisal
Diflunisal 250 mg po bid
Drug: diflunisal
Placebo comparator
Placebo
Placebo 1 po bid
Other: placebo

Interventions

Drugdiflunisal
given twice daily for 24 months
Otherplacebo
an inactive substance given twice daily for 24 months

What researchers measure

Primary outcomes

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).
Time frame: Baseline, 1 and 2 years

Secondary outcomes

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)
Time frame: Baseline, 1 and 2 years
Modified Body Mass Index (mBMI);
The product of body mass index (BMI) and serum albumin level (g/L) \[kg/M2xg/L\].
Time frame: 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.
Time frame: 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.
Time frame: Baseline, 1 and 2 years

Results

Posted Mar 17, 2017

Participant flow

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).

Participant flow — Overall Study
Milestone	Diflunisal	Placebo
Started	64	66
Completed	37	26
Not completed	27	40
Withdrew: Lack of efficacy	11	23
Withdrew: Liver transplant	7	9
Withdrew: Drug related adverse event (ae)	4	2
Withdrew: Non-drug related ae	3	2
Withdrew: Lost to follow-up	1	3
Withdrew: Non-compliance	1	0
Withdrew: Death	0	1

Outcome measures

PrimaryNeurologic 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).

Time frame:: Baseline, 1 and 2 years
Reported as:: Mean · units on a scale

Neurologic Impairment Score + 7 (NIS+7)
units on a scale	Diflunisal	Placebo
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)

Statistical analysis

Diflunisal vs Placebo · t-test, 2 sided · p = <0.001
Diflunisal vs Placebo · t-test, 2 sided · p = 0.02

SecondaryKumamoto 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)

Time frame:: Baseline, 1 and 2 years
Reported as:: Mean · units on a scale

Kumamoto Neurologic Scale;
units on a scale	Diflunisal	Placebo
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)

Statistical analysis

Diflunisal vs Placebo · t-test, 2 sided · p = 0.002
Diflunisal vs Placebo · t-test, 2 sided · p = 0.10

SecondaryModified Body Mass Index (mBMI);

The product of body mass index (BMI) and serum albumin level (g/L) \[kg/M2xg/L\].

Time frame:: Baseline, 1 and 2 years
Reported as:: Mean · kg/M2xg/L

Modified Body Mass Index (mBMI);
kg/M2xg/L	Diflunisal	Placebo
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)

Statistical analysis

Diflunisal vs Placebo · t-test, 2 sided · p = 0.21
Diflunisal vs Placebo · t-test, 2 sided · p = 0.43

SecondaryQuality 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.

Time frame:: Baseline, 1 and 2 years
Reported as:: Mean · units on a scale

Quality of Life Questionnaire: SF-36 Physical Component Score
units on a scale	Diflunisal	Placebo
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)

Statistical analysis

Diflunisal vs Placebo · t-test, 2 sided · p = 0.001
Diflunisal vs Placebo · t-test, 2 sided · p = 0.06

SecondaryQuality 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.

Time frame:: Baseline, 1 and 2 years
Reported as:: Mean · units on a scale

Quality of Life Questionnaire: SF-36 Mental Component Score
units on a scale	Diflunisal	Placebo
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)

Statistical analysis

Diflunisal vs Placebo · t-test, 2 sided · p = 0.06
Diflunisal vs Placebo · t-test, 2 sided · p = 0.37

Adverse events

Collected over Adverse event data were collected for 2 years or until study withdrawal.. Non-serious events are listed at a 0% frequency threshold.

Adverse event summary by group
Group	Deaths	Serious	Other
Diflunisal	—	3/64 (4.7%)	29/64 (45.3%)
Placebo	—	4/66 (6.1%)	27/66 (40.9%)

Most frequent serious events

Most frequent serious events
Event	Diflunisal	Placebo
Cardiac disordersCardiac disorders	2/64	1/66
Gastrointestinal disordersGastrointestinal disorders	1/64	2/66
Renal and urinary disordersRenal and urinary disorders	0/64	2/66
Injury, poisoning and procedural complicationsInjury, poisoning and procedural complications	1/64	0/66
Infections and infestationsInfections and infestations	0/64	1/66

Most frequent other events

Showing 10 of 23

Most frequent other events
Event	Diflunisal	Placebo
InfectionsInfections and infestations	24/64	27/66
GI disordersGastrointestinal disorders	23/64	25/66
Nervous system disordersNervous system disorders	23/64	20/66
Musculoskeletal and connective tissue disordersMusculoskeletal and connective tissue disorders	19/64	8/66
General disordersGeneral disorders	19/64	7/66
Cardiac disordersCardiac disorders	15/64	9/66
Injury, poisoning and procedural complicationsInjury, poisoning and procedural complications	13/64	9/66
Respiratory disordersRespiratory, thoracic and mediastinal disorders	12/64	11/66
Renal and urinary disordersRenal and urinary disorders	10/64	12/66
InvestigationsInvestigations	11/64	11/66

Baseline characteristics

Age, Continuous
Age, Continuous(years)	Diflunisal	Placebo	Total
Mean	60.3 ± 11.7	59.2 ± 12.2	59.7 ± 11.9

Sex: Female, Male
Sex: Female, Male(Participants)	Diflunisal	Placebo	Total
Female	21	22	43
Male	43	44	87

Race (NIH/OMB)
Race (NIH/OMB)(Participants)	Diflunisal	Placebo	Total
American Indian or Alaska Native	0	0	0
Asian	8	6	14
Native Hawaiian or Other Pacific Islander	0	0	0
Black or African American	1	5	6
White	52	50	102
More than one race	3	4	7
Unknown or Not Reported	0	1	1

Region of Enrollment
Region of Enrollment(participants)	Diflunisal	Placebo	Total
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
NIS+7 score(units on a scale)	Diflunisal	Placebo	Total
Mean	51.6 ± 42.8	59.0 ± 50	55.3 ± 46.5

Kumamoto score
Kumamoto score(units on a scale)	Diflunisal	Placebo	Total
Mean	15.3 ± 10.8	16.7 ± 13.5	16.0 ± 12.2

Modified BMI
Modified BMI(kg/M2 x g/L)	Diflunisal	Placebo	Total
Mean	1024.4 ± 226.3	1019 ± 255	1021.7 ± 240.4

SF-36 physical component score
SF-36 physical component score(units on a scale)	Diflunisal	Placebo	Total
Mean	35.9 ± 11.6	34.8 ± 11	35.4 ± 11.3

1 further baseline measures are reported on the registry.

Study locations

8 sites

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

References and documents

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. PubMed 24368466 ↗

Individual participant data

Plan to share: No — A manuscript analyzing cardiac outcomes is being prepared. We will consider IPD after the manuscript is complete and accepted.

Updates

Tracking since Sep 25, 2026

No changes since tracking began. The registry record was last updated on Mar 17, 2017, before this site started recording changes on Sep 25, 2026. Its history is on ClinicalTrials.gov ↗

Registry details

Key details

Study ID: NCT00294671
Lead sponsor: Boston University
Collaborators: Food and Drug Administration (FDA), National Institute of Neurological Disorders and Stroke (NINDS)
Responsible party: John L. Berk (Principal Investigator, Boston University) — Principal investigator
First posted: Feb 22, 2006
Start date: Feb 2006
Primary completion: Dec 2012
Completion: Dec 2012
Results posted: Mar 17, 2017
Last update: Mar 17, 2017

Study contacts

John L. Berk, MD

principal investigator · Boston University

Oversight

Data monitoring committee: Yes

View the source record on ClinicalTrials.gov ↗

Not currently enrolling

This study is completed, as verified in Jan 2017. You cannot join it, but the record below documents what was studied.

Follow this study

Get an email when the registry record changes — status, dates, results — or when someone posts here.

Discussion

Questions and observations about this study, from anyone following it. Not medical advice, and not a channel to the study team — their contact details are on the registry record.

Sign in to join the discussion. Reading takes no account; posting does. You choose a display name, and a pseudonym is the default.

Nothing here yet. If you are running this trial, taking part in it, or weighing whether to, this is the place to say so.

Other studies in this condition

Polyneuropathies→

Other studies from this sponsor

Boston University

Start the discussion

The Effect of Diflunisal on Familial Amyloidosis

Study summary

Conditions studied

Browse trials for

Keywords

In context

Polyneuropathies

Lead sponsor

Who can participate

✓Inclusion criteria

✕Exclusion criteria

Study design

Study arms

Interventions

What researchers measure

Primary outcomes

Secondary outcomes

Results

Participant flow

Outcome measures

Adverse events

Baseline characteristics

Study locations

References and documents

Publications

Individual participant data

Updates

Registry details

Key details

Study contacts

Oversight

Not currently enrolling

Follow this study

Discussion

Other studies in this condition

Other studies from this sponsor

Inclusion criteria

Exclusion criteria