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| ID | Type | Description | Link |
|---|---|---|---|
| FD R 002532 | Other Grant/Funding Number | FDA Office of Orphan Products Development (OOPD) | |
| R01NS051306 | U.S. NIH Grant/Contract | View source |
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| Name | Class |
|---|---|
| Food and Drug Administration (FDA) | FED |
| National Institute of Neurological Disorders and Stroke (NINDS) | NIH |
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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)
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Diflunisal | Active Comparator | Diflunisal 250 mg po bid |
|
| Placebo | Placebo Comparator | Placebo 1 po bid |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| diflunisal | Drug | given twice daily for 24 months |
| |
| placebo |
| Measure | Description | Time Frame |
|---|---|---|
| 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). | Baseline, 1 and 2 years |
| Measure | Description | Time Frame |
|---|---|---|
| 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) | Baseline, 1 and 2 years |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| John L. Berk, MD | Boston University | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Amyloidosis Center, Boston Medical Center | Boston | Massachusetts | 02118 | United States | ||
| Mayo Clinic Rochester |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 24368466 | Derived | 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. |
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A manuscript analyzing cardiac outcomes is being prepared. We will consider IPD after the manuscript is complete and accepted.
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All enrolled participants were randomized to treatment groups.
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).
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| ID | Title | Description |
|---|---|---|
| FG000 | Diflunisal | Diflunisal 250 mg taken by mouth twice daily for 24 months |
| FG001 | Placebo | Placebo, an inactive substance, taken by mouth twice daily for 24 months |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Diflunisal | Diflunisal 250 mg taken by mouth twice daily for 24 months |
| BG001 | Placebo | Placebo, an inactive substance, taken by mouth twice daily for 24 months |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | 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). | Longitudinal analysis examined data from all 130 participants using intention-to-treat principles. | Posted | Mean | 95% Confidence Interval | units on a scale | Baseline, 1 and 2 years |
|
Adverse event data were collected for 2 years or until study withdrawal.
Adverse events were collected and analyzed by affected organ system.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Diflunisal | Diflunisal 250 mg taken by mouth twice daily for 24 months |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Gastrointestinal disorders | Gastrointestinal disorders | MedDRA 15.1 | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Infections | Infections and infestations | MedDRA 15.1 | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. John L. Berk | Amyloidosis Center, Boston Medical Center | 617-638-4494 | jberk@bu.edu |
| ID | Term |
|---|---|
| D028227 | Amyloid Neuropathies, Familial |
| D028226 | Amyloidosis, Familial |
| D000686 | Amyloidosis |
| D010523 | Peripheral Nervous System Diseases |
| ID | Term |
|---|---|
| D020271 | Heredodegenerative Disorders, Nervous System |
| D019636 | Neurodegenerative Diseases |
| D009422 | Nervous System Diseases |
| D017772 | Amyloid Neuropathies |
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| ID | Term |
|---|---|
| D004061 | Diflunisal |
| ID | Term |
|---|---|
| D012459 | Salicylates |
| D062385 | Hydroxybenzoates |
| D010636 | Phenols |
| D001555 | Benzene Derivatives |
Not provided
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| Other |
an inactive substance given twice daily for 24 months |
|
| Modified Body Mass Index (mBMI); | The product of body mass index (BMI) and serum albumin level (g/L) [kg/M2xg/L]. | 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. | 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. | Baseline, 1 and 2 years |
| 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 | Umeå | SE-901 86 | Sweden |
| King's College Hospital | London | SE5 9RS | United Kingdom |
| Drug related adverse event (AE) |
|
| Non-drug related AE |
|
| Lost to Follow-up |
|
| Non-compliance |
|
| Death |
|
| BG002 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| NIS+7 score | Higher scores indicating greater neurologic deficits (0=no neurologic impairment, 270=no detectable peripheral neurologic function) | Mean | Standard Deviation | units on a scale |
|
| Kumamoto score | Higher scores indicating greater neurologic and end organ deficits (0=no neurologic deficits, 102=no detectable peripheral neurologic function) | Mean | Standard Deviation | units on a scale |
|
| Modified BMI | The product of BMI and serum albumin (g/L). Lower scores indicate worse nutritional status. | Mean | Standard Deviation | kg/M2 x g/L |
|
| SF-36 physical component score | Higher scores indicate greater physical quality of life, scale from 0 to 100 points | Mean | Standard Deviation | units on a scale |
|
| SF-36 mental component score | Higher scores indicate greater mental quality of life, scale 0-100 points | Mean | Standard Deviation | units on a scale |
|
|
|
|
| Secondary | 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) | Posted | Mean | 95% Confidence Interval | units on a scale | Baseline, 1 and 2 years |
|
|
|
|
| Secondary | Modified Body Mass Index (mBMI); | The product of body mass index (BMI) and serum albumin level (g/L) [kg/M2xg/L]. | Posted | Mean | 95% Confidence Interval | kg/M2xg/L | Baseline, 1 and 2 years |
|
|
|
|
| Secondary | 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. | Longitudinal analysis examined data from all 130 participants using intention-to-treat principles. | Posted | Mean | 95% Confidence Interval | units on a scale | Baseline, 1 and 2 years |
|
|
|
|
| Secondary | 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. | Posted | Mean | 95% Confidence Interval | units on a scale | Baseline, 1 and 2 years |
|
|
|
|
| 3 |
| 64 |
| 29 |
| 64 |
| EG001 | Placebo | Placebo, an inactive substance, taken by mouth twice daily for 24 months | 4 | 66 | 27 | 66 |
| Infections and infestations | Infections and infestations | MedDRA 15.1 | Systematic Assessment |
|
| Cardiac disorders | Cardiac disorders | MedDRA 15.1 | Systematic Assessment |
|
| Injury, poisoning and procedural complications | Injury, poisoning and procedural complications | MedDRA 15.1 | Systematic Assessment |
|
| Renal and urinary disorders | Renal and urinary disorders | MedDRA 15.1 | Systematic Assessment |
|
| GI disorders | Gastrointestinal disorders | MedDRA 15.1 | Systematic Assessment |
|
| Nervous system disorders | Nervous system disorders | MedDRA 15.1 | Systematic Assessment |
|
| Musculoskeletal and connective tissue disorders | Musculoskeletal and connective tissue disorders | MedDRA 15.1 | Systematic Assessment |
|
| General disorders | General disorders | MedDRA 15.1 | Systematic Assessment |
|
| Cardiac disorders | Cardiac disorders | MedDRA 15.1 | Systematic Assessment |
|
| Respiratory disorders | Respiratory, thoracic and mediastinal disorders | MedDRA 15.1 | Systematic Assessment |
|
| Injury, poisoning and procedural complications | Injury, poisoning and procedural complications | MedDRA 15.1 | Systematic Assessment |
|
| Investigations | Investigations | MedDRA 15.1 | Systematic Assessment |
|
| Renal and urinary disorders | Renal and urinary disorders | MedDRA 15.1 | Systematic Assessment |
|
| Vascular disorders | Vascular disorders | MedDRA 15.1 | Systematic Assessment |
|
| Eye disorders | Eye disorders | MedDRA 15.1 | Systematic Assessment |
|
| Metabolism and nutrition disorders | Metabolism and nutrition disorders | MedDRA 15.1 | Systematic Assessment |
|
| Psychiatric disorders | Psychiatric disorders | MedDRA 15.1 | Systematic Assessment |
|
| Skin and subcutaneous tissue disorders | Skin and subcutaneous tissue disorders | MedDRA 15.1 | Systematic Assessment |
|
| Surgical and medical procedures | Surgical and medical procedures | MedDRA 15.1 | Systematic Assessment |
|
| Blood and lymphatic system disorders | Blood and lymphatic system disorders | MedDRA 15.1 | Systematic Assessment |
|
| Neoplasms | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | MedDRA 15.1 | Systematic Assessment |
|
| Ear and labyrinth disorders | Ear and labyrinth disorders | MedDRA 15.1 | Systematic Assessment |
|
| Endocrine disorders | Endocrine disorders | MedDRA 15.1 | Systematic Assessment |
|
| Hepatobiliary disorders | Hepatobiliary disorders | MedDRA 15.1 | Systematic Assessment |
|
| Immune system disorders | Immune system disorders | MedDRA 15.1 | Systematic Assessment |
|
| Reproductive system and breast disorders | Reproductive system and breast disorders | MedDRA 15.1 | Systematic Assessment |
|
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| D009468 | Neuromuscular Diseases |
| D030342 | Genetic Diseases, Inborn |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
| D008661 | Metabolism, Inborn Errors |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
| D057165 | Proteostasis Deficiencies |
| D006841 |
| Hydrocarbons, Aromatic |
| D006844 | Hydrocarbons, Cyclic |
| D006838 | Hydrocarbons |
| D009930 | Organic Chemicals |
| t-test, 2 sided |
| 0.10 |
| Superiority or Other |
| t-test, 2 sided |
| 0.43 |
| Superiority or Other |
| t-test, 2 sided |
| 0.06 |
| Superiority or Other |
| t-test, 2 sided |
| 0.37 |
| Superiority or Other |