Familial Amyloid PolyneuropathyPhase 2/3NCT00294671
The Effect of Diflunisal on Familial Amyloidosis
A Phase 2/3 study testing diflunisal in people with Familial Amyloid Polyneuropathy and Familial Amyloidosis, run by Boston University at 8 sites in 5 countries.
Trial 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 more about this study
- Who is it for?
- Ages 18 to 75 years
- Conditions the study is for
- Familial Amyloid Polyneuropathy, Familial Amyloidosis
- What is being tested?
- diflunisal
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 130 participants
- Where
- 8 sitesin 5 countries
- Study dates
- Feb 2006to Dec 2012
- Phase
- Phase 2/3
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 75 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Age 18 to 75 years
- Biopsy proven amyloidosis
- Genotyping of variant transthyretin
- Signs of peripheral or autonomic neuropathy
Who cannot join
- 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
Trial locations and contacts
8 sites in 5 countries.
8 sites in 5 countries
United States3 sites
Amyloidosis Center, Boston Medical Center
Boston, Massachusetts, 02118
Mount Sinai School of Medicine, Department of Medicine
New York, New York, 10029-6574
Mayo Clinic Rochester
Rochester, Minnesota, 55905
Japan2 sites
Kumamoto University
Kumamoto, 860-0811
Shinshu University
Matsumoto, 390-8621
About this study
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.
- Being tested
- diflunisal, placebo
- Keywords
- familial amyloid polyneuropathy, familial amyloidosis, diflunisal, amyloidosis, transthyretin, peripheral neuropathy, autonomic neuropathy, amyloid cardiomyopathy
- Medical subject headings
- Amyloid Neuropathies, Familial, Amyloidosis, Familial, Amyloidosis, Peripheral Nervous System Diseases
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
diflunisalDrug
given twice daily for 24 months
placeboOther
an inactive substance given twice daily for 24 months
| Study group | Role | What they receive |
|---|---|---|
| Diflunisal | Active comparator | Diflunisal 250 mg po bid Receives: Drug: diflunisal |
| Placebo | Placebo comparator | Placebo 1 po bid Receives: Other: placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
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).
Measured: Baseline, 1 and 2 years
Secondary outcomes (4)
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)
Measured: 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].
Measured: 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.
Measured: 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.
Measured: Baseline, 1 and 2 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted22 Feb 2006 (estimated)
- Study startFeb 2006
- Primary completionDec 2012
- Study completionDec 2012
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Familial Amyloid PolyneuropathyStudies of the same condition, open and under way.
- More trials run by Boston UniversityThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2/3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind
- Who is masked
- Participant, Investigator
- Enrolment
- 130 participants (actual)
Sponsor and investigators
- Lead sponsor
- Boston University
- Sponsor type
- University, hospital or other
- Collaborators
- Food and Drug Administration (FDA), National Institute of Neurological Disorders and Stroke (NINDS)
- Responsible party
- Principal investigator, John L. Berk, Boston University
- Investigators
- John L. Berk, MD, Principal investigator, Boston University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00294671
- Sponsor's protocol ID
- R01NS051306
- Other IDs
- FD R 002532, R01NS051306
- Status last verified
- Jan 2017
- First submitted
- 21 Feb 2006
- Last updated
- 17 Mar 2017
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- Individual data sharing
- No: A manuscript analyzing cardiac outcomes is being prepared. We will consider IPD after the manuscript is complete and accepted.
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
Study at a glance
From the registry record, last updated by the sponsor on 17 Mar 2017. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- The Effect of Diflunisal on Familial Amyloidosis
- ClinicalTrials.gov ID
- NCT00294671
- Acronym / sponsor ID
- R01NS051306
- Keywords
- familial amyloid polyneuropathy, familial amyloidosis, diflunisal, amyloidosis, transthyretin, peripheral neuropathy, autonomic neuropathy, amyloid cardiomyopathy
- Phase
- Phase 2/3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 130 participants (actual)
- Lead sponsor
- Boston UniversityUniversity, hospital or other
- Collaborators
- Food and Drug Administration (FDA), National Institute of Neurological Disorders and Stroke (NINDS)
- Study start
- Feb 2006
- Primary completion
- Dec 2012 (actual)
- Study completion
- Dec 2012 (actual)
- First posted
- 22 Feb 2006 (estimated)
- Results
- Posted 17 Mar 2017
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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 design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind (participant, investigator)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Diflunisal | Active comparator | Drug: diflunisalDiflunisal 250 mg po bid |
| Placebo | Placebo comparator | Other: placeboPlacebo 1 po bid |
Who may qualify
- Ages
- 18 to 75 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (4 listed)
- Age 18 to 75 years
- Biopsy proven amyloidosis
- Genotyping of variant transthyretin
- Signs of peripheral or autonomic neuropathy
Key exclusion criteria (8 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| diflunisalgiven twice daily for 24 months | Drug | Diflunisal |
| placeboan inactive substance given twice daily for 24 months | Other | Placebo |
Primary outcome
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).
4 secondary outcomes
Kumamoto Neurologic Scale;
Time frame: Baseline, 1 and 2 years
Modified Body Mass Index (mBMI);
Time frame: Baseline, 1 and 2 years
Quality of Life Questionnaire: SF-36 Physical Component Score
Time frame: Baseline, 1 and 2 years
Quality of Life Questionnaire: SF-36 Mental Component Score
Time frame: Baseline, 1 and 2 years
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 17 Mar 2017.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 24368466Berk 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.
- Individual participant dataSharing planned: No. A manuscript analyzing cardiac outcomes is being prepared. We will consider IPD after the manuscript is complete and accepted.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
John L. Berk, MD principal investigator
Boston University
8 sites in 5 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2/3 study testing diflunisal in people with Familial Amyloid Polyneuropathy and Familial Amyloidosis, run by Boston University at 8 sites in 5 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 8 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 17 Mar 2017. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 8 sites in United States, Japan, Italy, Sweden, United Kingdom. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 17 Mar 2017). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Neurologic Impairment Score + 7 (NIS+7) (time frame: Baseline, 1 and 2 years). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00294671, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 17 Mar 2017.