Familial Amyloidosis, Familial Amyloid Polyneuropathy
Conditions
Keywords
familial amyloid polyneuropathy, familial amyloidosis, diflunisal, amyloidosis, transthyretin, peripheral neuropathy, autonomic neuropathy, amyloid cardiomyopathy
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.
Interventions
DRUGdiflunisal
given twice daily for 24 months
OTHERplacebo
an inactive substance given twice daily for 24 months
Sponsors
Food and Drug Administration (FDA)
National Institute of Neurological Disorders and Stroke (NINDS)
Boston University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
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
* 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Neurologic Impairment Score + 7 (NIS+7) | 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). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Kumamoto Neurologic Scale; | 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); | 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 | 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 | 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. |
Countries
Italy, Japan, Sweden, United Kingdom, United States
Participant flow
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.
Participants by arm
| Arm | Count |
|---|---|
| Diflunisal Diflunisal 250 mg taken by mouth twice daily for 24 months | 64 |
| Placebo Placebo, an inactive substance, taken by mouth twice daily for 24 months | 66 |
| Total | 130 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 0 | 1 |
| Overall Study | Drug related adverse event (AE) | 4 | 2 |
| Overall Study | Lack of Efficacy | 11 | 23 |
| Overall Study | Liver transplant | 7 | 9 |
| Overall Study | Lost to Follow-up | 1 | 3 |
| Overall Study | Non-compliance | 1 | 0 |
| Overall Study | Non-drug related AE | 3 | 2 |
Baseline characteristics
| Characteristic | Placebo | Diflunisal | Total |
|---|---|---|---|
| Age, Continuous | 59.2 years STANDARD_DEVIATION 12.2 | 60.3 years STANDARD_DEVIATION 11.7 | 59.7 years STANDARD_DEVIATION 11.9 |
| Kumamoto score | 16.7 units on a scale STANDARD_DEVIATION 13.5 | 15.3 units on a scale STANDARD_DEVIATION 10.8 | 16.0 units on a scale STANDARD_DEVIATION 12.2 |
| Modified BMI | 1019 kg/M2 x g/L STANDARD_DEVIATION 255 | 1024.4 kg/M2 x g/L STANDARD_DEVIATION 226.3 | 1021.7 kg/M2 x g/L STANDARD_DEVIATION 240.4 |
| NIS+7 score | 59.0 units on a scale STANDARD_DEVIATION 50 | 51.6 units on a scale STANDARD_DEVIATION 42.8 | 55.3 units on a scale STANDARD_DEVIATION 46.5 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 6 Participants | 8 Participants | 14 Participants |
| Race (NIH/OMB) Black or African American | 5 Participants | 1 Participants | 6 Participants |
| Race (NIH/OMB) More than one race | 4 Participants | 3 Participants | 7 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 50 Participants | 52 Participants | 102 Participants |
| Region of Enrollment Italy | 11 participants | 10 participants | 21 participants |
| Region of Enrollment Japan | 4 participants | 5 participants | 9 participants |
| Region of Enrollment Sweden | 12 participants | 12 participants | 24 participants |
| Region of Enrollment United Kingdom | 4 participants | 3 participants | 7 participants |
| Region of Enrollment United States | 35 participants | 34 participants | 69 participants |
| Sex: Female, Male Female | 22 Participants | 21 Participants | 43 Participants |
| Sex: Female, Male Male | 44 Participants | 43 Participants | 87 Participants |
| SF-36 mental component score | 46.5 units on a scale STANDARD_DEVIATION 11.8 | 46.6 units on a scale STANDARD_DEVIATION 14.1 | 46.6 units on a scale STANDARD_DEVIATION 12.9 |
| SF-36 physical component score | 34.8 units on a scale STANDARD_DEVIATION 11 | 35.9 units on a scale STANDARD_DEVIATION 11.6 | 35.4 units on a scale STANDARD_DEVIATION 11.3 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 29 / 64 | 27 / 66 |
| serious Total, serious adverse events | 3 / 64 | 4 / 66 |
Outcome results
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).
Time frame: Baseline, 1 and 2 years
Population: Longitudinal analysis examined data from all 130 participants using intention-to-treat principles.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Diflunisal | Neurologic Impairment Score + 7 (NIS+7) | Change from baseline to 2 years | 8.2 units on a scale |
| Diflunisal | Neurologic Impairment Score + 7 (NIS+7) | Change from baseline to 1 year | 6.2 units on a scale |
| Placebo | Neurologic Impairment Score + 7 (NIS+7) | Change from baseline to 2 years | 26.3 units on a scale |
| Placebo | Neurologic Impairment Score + 7 (NIS+7) | Change from baseline to 1 year | 12.5 units on a scale |
Comparison: Longitudinal analysis of the difference between placebo and diflunisal treatment groups in NIS+7 change from baseline to 2 years.p-value: <0.001t-test, 2 sided
Comparison: Longitudinal analysis of the difference between placebo and diflunisal treatment groups in NIS+7 change from baseline to 1years.p-value: 0.02t-test, 2 sided
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)
Time frame: Baseline, 1 and 2 years
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Diflunisal | Kumamoto Neurologic Scale; | Change from baseline to 2 years | 3.1 units on a scale |
| Diflunisal | Kumamoto Neurologic Scale; | Change from baseline to 1 year | 1.9 units on a scale |
| Placebo | Kumamoto Neurologic Scale; | Change from baseline to 2 years | 8.0 units on a scale |
| Placebo | Kumamoto Neurologic Scale; | Change from baseline to 1 year | 4.1 units on a scale |
Comparison: Longitudinal analysis of the difference between placebo and diflunisal treatment groups in Kumamoto score change from baseline to 2 years.p-value: 0.002t-test, 2 sided
Comparison: Longitudinal analysis of the difference between placebo and diflunisal treatment groups in Kumamoto score change from baseline to 1 year.p-value: 0.1t-test, 2 sided
Secondary
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
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Diflunisal | Modified Body Mass Index (mBMI); | Change from baseline to 2 years | -33.7 kg/M2xg/L |
| Diflunisal | Modified Body Mass Index (mBMI); | Change from baseline to 1 year | -18.7 kg/M2xg/L |
| Placebo | Modified Body Mass Index (mBMI); | Change from baseline to 2 years | -67.9 kg/M2xg/L |
| Placebo | Modified Body Mass Index (mBMI); | Change from baseline to 1 year | -38.5 kg/M2xg/L |
Comparison: Longitudinal analysis of the difference between placebo and diflunisal treatment groups in mBMI change from baseline to 2 years.p-value: 0.21t-test, 2 sided
Comparison: Longitudinal analysis of the difference between placebo and diflunisal treatment groups in mBMI change from baseline to 1 year.p-value: 0.43t-test, 2 sided
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.
Time frame: Baseline, 1 and 2 years
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Diflunisal | Quality of Life Questionnaire: SF-36 Mental Component Score | Change from baseline to 2 years | 3.5 units on a scale |
| Diflunisal | Quality of Life Questionnaire: SF-36 Mental Component Score | Change from baseline to 1 year | 2.5 units on a scale |
| Placebo | Quality of Life Questionnaire: SF-36 Mental Component Score | Change from baseline to 2 years | -0.9 units on a scale |
| Placebo | Quality of Life Questionnaire: SF-36 Mental Component Score | Change from baseline to 1 year | 0.8 units on a scale |
Comparison: Longitudinal analysis of the difference between placebo and diflunisal treatment groups in SF-36 mental component change from baseline to 2 years.p-value: 0.06t-test, 2 sided
Comparison: Longitudinal analysis of the difference between placebo and diflunisal treatment groups in SF-36 mental component change from baseline to 1 year.p-value: 0.37t-test, 2 sided
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.
Time frame: Baseline, 1 and 2 years
Population: Longitudinal analysis examined data from all 130 participants using intention-to-treat principles.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Diflunisal | Quality of Life Questionnaire: SF-36 Physical Component Score | Change from baseline to 1 year | 0.7 units on a scale |
| Diflunisal | Quality of Life Questionnaire: SF-36 Physical Component Score | Change from baseline to 2 years | 1.2 units on a scale |
| Placebo | Quality of Life Questionnaire: SF-36 Physical Component Score | Change from baseline to 1 year | -1.9 units on a scale |
| Placebo | Quality of Life Questionnaire: SF-36 Physical Component Score | Change from baseline to 2 years | -4.9 units on a scale |
Comparison: Longitudinal analysis of the difference between placebo and diflunisal treatment groups in SF-36 physical component change from baseline to 2 years.p-value: 0.001t-test, 2 sided
Comparison: Longitudinal analysis of the difference between placebo and diflunisal treatment groups in SF-36 physical component change from baseline to 1 year.p-value: 0.06t-test, 2 sided