ATTR Amyloidosis, Familial Amyloid Neuropathies, Familial Amyloidotic Polyneuropathy (FAP), Transthyretin (TTR)-Mediated Amyloidosis
Conditions
Keywords
FAP, Familial Amyloidotic Polyneuropathy, ATTR Amyloidosis, Orthotopic Liver Transplant, RNAi therapeutic
Brief summary
The purpose of this study was to evaluate the safety and effectiveness of revusiran (ALN-TTRSC) in adults with transthyretin-mediated amyloidosis (ATTR), whose disease has continued to worsen after liver transplantation. Dosing has been discontinued; patients are being followed-up for safety.
Interventions
DRUGRevusiran
500mg Revusiran by subcutaneous (sc) injection
Sponsors
Alnylam Pharmaceuticals
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Diagnosis of FAP (familial amyloidotic polyneuropathy) with documented TTR mutation * Received an orthotopic liver transplant ≥12 months before the date of informed consent * An increase in polyneuropathy disability (PND) score post-transplant * Polyneuropathy Disability score of ≤3b
Exclusion criteria
* New York Heart Association (NYHA) classification of \>2 * Other known causes of sensorimotor or autonomic neuropathy (eg, autoimmune disease)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage Change From Baseline in Serum TTR at Month 6 | Month 6 | A negative percentage change from baseline at Month 6 indicates a reduction in serum TTR level. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage Change From Baseline in Serum TTR Over 18 Months | Weeks 3, 7, 12, 18, 24, 26 (Month 6), 39 (Month 9), 52 (Month 12), 57, 78 (Month 18) | A negative percentage change from baseline indicates a reduction in serum TTR level. |
| Change From Baseline in Modified Neurological Impairment Score (mNIS +7) Composite Score Over 18 Months | Baseline, Months 6, 12, 18 | The mNIS+7 is a composite score that measures neurologic impairment which includes the following components: physical exam of lower limbs, upper limbs and cranial nerves to assess motor strength/weakness, electrophysiologic measurement of small and large nerve fiber function, sensory testing and postural blood pressure. The minimum and maximum values are 0 and 304, respectively. A higher score indicates a worse outcome. A negative change from baseline indicates an improvement. |
| Norfolk Quality of Life-Diabetic Neuropathy (QoL-DN) Questionnaire Score | Baseline, Months 6, 12, 18 | The Norfolk QoL-DN questionnaire is a standardized 35-item patient-reported outcomes measure that is sensitive to the different features of diabetic neuropathy - small fiber, large fiber, and autonomic nerve function. The minimum and maximum values are -4 and 136, respectively. A higher score indicates a worse outcome. |
| Number of Participants in Each Polyneuropathy Disability (PND) Stage Based on Worst Post-Baseline Score | Baseline, Months 6, 12, 18 | PND Scores: Stage 0: No symptoms, Stage 1: Sensory disturbances but preserved walking capabilities, Stage 2: Impaired walking capacity, but ability to walk without a stick or crutches, Stage 3A/B: Walking with help of 1 or 2 sticks or crutches, Stage 4: confined to wheel chair. For each stage (0-4) at baseline, the number of participants is presented at their worst post-baseline score for each stage (0-4) post-baseline. Worst post-baseline is defined the highest PND classification for a participant recorded after the first dose of study drug. |
Countries
France, Germany, Portugal, Spain, Sweden, United Kingdom
Participant flow
Recruitment details
A total of 12 participants with hereditary Transthyretin-mediated Amyloidosis (ATTR) with polyneuropathy who had neuropathy progression following post-orthotopic liver transplant (OLT) were enrolled and treated in this study.
Participants by arm
| Arm | Count |
|---|---|
| All Patients All patients who received at least 1 dose of revusiran | 12 |
| Total | 12 |
Baseline characteristics
| Characteristic | All Patients |
|---|---|
| Age, Continuous | 55.8 years STANDARD_DEVIATION 8.65 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 10 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Familial Amyloidotic Polyneuropathy (FAP) Stage FAP Stage II: Assistance with ambulation required | 9 Participants |
| Familial Amyloidotic Polyneuropathy (FAP) Stage FAP Stage III: Wheelchair-bound or bedridden | 0 Participants |
| Familial Amyloidotic Polyneuropathy (FAP) Stage FAP Stage I: Unimpaired ambulation | 3 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 12 Participants |
| Serum Transthyretin (TTR) | 192.3 micrograms/milliliter (μg/mL) STANDARD_DEVIATION 43.28 |
| Sex: Female, Male Female | 3 Participants |
| Sex: Female, Male Male | 9 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 2 / 12 |
| other Total, other adverse events | 11 / 12 |
| serious Total, serious adverse events | 8 / 12 |
Outcome results
Primary
Percentage Change From Baseline in Serum TTR at Month 6
A negative percentage change from baseline at Month 6 indicates a reduction in serum TTR level.
Time frame: Month 6
Population: Safety analysis set: All participants who received at least a single dose of study drug and for whom data were collected at Month 6.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| All Patients | Percentage Change From Baseline in Serum TTR at Month 6 | -72.0 percentage change from baseline in TTR | Standard Deviation 18.39 |
Secondary
Change From Baseline in Modified Neurological Impairment Score (mNIS +7) Composite Score Over 18 Months
The mNIS+7 is a composite score that measures neurologic impairment which includes the following components: physical exam of lower limbs, upper limbs and cranial nerves to assess motor strength/weakness, electrophysiologic measurement of small and large nerve fiber function, sensory testing and postural blood pressure. The minimum and maximum values are 0 and 304, respectively. A higher score indicates a worse outcome. A negative change from baseline indicates an improvement.
Time frame: Baseline, Months 6, 12, 18
Population: Safety analysis set: All participants who received at least a single dose of study drug and for whom data were collected at each time point. Data collection was limited due to the discontinuation of the drug treatment early in the study as per protocol amendment.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| All Patients | Change From Baseline in Modified Neurological Impairment Score (mNIS +7) Composite Score Over 18 Months | Baseline | 90.4 score on a scale | Standard Deviation 43.76 |
| All Patients | Change From Baseline in Modified Neurological Impairment Score (mNIS +7) Composite Score Over 18 Months | Change from baseline at Month 6 | 6.9 score on a scale | Standard Deviation 10.42 |
Secondary
Norfolk Quality of Life-Diabetic Neuropathy (QoL-DN) Questionnaire Score
The Norfolk QoL-DN questionnaire is a standardized 35-item patient-reported outcomes measure that is sensitive to the different features of diabetic neuropathy - small fiber, large fiber, and autonomic nerve function. The minimum and maximum values are -4 and 136, respectively. A higher score indicates a worse outcome.
Time frame: Baseline, Months 6, 12, 18
Population: Safety analysis set: All participants who received at least a single dose of study drug and for whom data were collected at each time point. Data collection was limited due to the discontinuation of the drug treatment early in the study as per protocol amendment.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| All Patients | Norfolk Quality of Life-Diabetic Neuropathy (QoL-DN) Questionnaire Score | Baseline | 61.3 score on a scale | Standard Deviation 24.86 |
| All Patients | Norfolk Quality of Life-Diabetic Neuropathy (QoL-DN) Questionnaire Score | Month 6 | 77.1 score on a scale | Standard Deviation 31.06 |
Secondary
Number of Participants in Each Polyneuropathy Disability (PND) Stage Based on Worst Post-Baseline Score
PND Scores: Stage 0: No symptoms, Stage 1: Sensory disturbances but preserved walking capabilities, Stage 2: Impaired walking capacity, but ability to walk without a stick or crutches, Stage 3A/B: Walking with help of 1 or 2 sticks or crutches, Stage 4: confined to wheel chair. For each stage (0-4) at baseline, the number of participants is presented at their worst post-baseline score for each stage (0-4) post-baseline. Worst post-baseline is defined the highest PND classification for a participant recorded after the first dose of study drug.
Time frame: Baseline, Months 6, 12, 18
Population: Safety analysis set: All participants who received at least a single dose of study drug and for whom data were collected post-baseline. Data collection was limited due to the discontinuation of the drug treatment early in the study as per protocol amendment.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| All Patients | Number of Participants in Each Polyneuropathy Disability (PND) Stage Based on Worst Post-Baseline Score | Baseline Stage 0, Post-baseline Stage 2 | 0 Participants |
| All Patients | Number of Participants in Each Polyneuropathy Disability (PND) Stage Based on Worst Post-Baseline Score | Baseline Stage 0, Post-baseline Stage 3A/B | 0 Participants |
| All Patients | Number of Participants in Each Polyneuropathy Disability (PND) Stage Based on Worst Post-Baseline Score | Baseline Stage 1, Post-baseline Stage 0 | 0 Participants |
| All Patients | Number of Participants in Each Polyneuropathy Disability (PND) Stage Based on Worst Post-Baseline Score | Baseline Stage 1, Post-baseline Stage 1 | 1 Participants |
| All Patients | Number of Participants in Each Polyneuropathy Disability (PND) Stage Based on Worst Post-Baseline Score | Baseline Stage 1, Post-baseline Stage 2 | 0 Participants |
| All Patients | Number of Participants in Each Polyneuropathy Disability (PND) Stage Based on Worst Post-Baseline Score | Baseline Stage 3A/B, Post-baseline Stage 1 | 0 Participants |
| All Patients | Number of Participants in Each Polyneuropathy Disability (PND) Stage Based on Worst Post-Baseline Score | Baseline Stage 3A/B, Post-baseline Stage 2 | 1 Participants |
| All Patients | Number of Participants in Each Polyneuropathy Disability (PND) Stage Based on Worst Post-Baseline Score | Baseline Stage 3A/B, Post-baseline Stage 3A/B | 6 Participants |
| All Patients | Number of Participants in Each Polyneuropathy Disability (PND) Stage Based on Worst Post-Baseline Score | Baseline Stage 3A/B, Post-baseline Stage 4 | 2 Participants |
| All Patients | Number of Participants in Each Polyneuropathy Disability (PND) Stage Based on Worst Post-Baseline Score | Baseline Stage 4, Post-baseline Stage 3A/B | 0 Participants |
| All Patients | Number of Participants in Each Polyneuropathy Disability (PND) Stage Based on Worst Post-Baseline Score | Baseline Stage 4, Post-baseline Stage 4 | 0 Participants |
| All Patients | Number of Participants in Each Polyneuropathy Disability (PND) Stage Based on Worst Post-Baseline Score | Baseline Stage 0, Post-baseline Stage 0 | 0 Participants |
| All Patients | Number of Participants in Each Polyneuropathy Disability (PND) Stage Based on Worst Post-Baseline Score | Baseline Stage 0, Post-baseline Stage 1 | 0 Participants |
| All Patients | Number of Participants in Each Polyneuropathy Disability (PND) Stage Based on Worst Post-Baseline Score | Baseline Stage 0, Post-baseline Stage 4 | 0 Participants |
| All Patients | Number of Participants in Each Polyneuropathy Disability (PND) Stage Based on Worst Post-Baseline Score | Baseline Stage 1, Post-baseline Stage 3A/B | 0 Participants |
| All Patients | Number of Participants in Each Polyneuropathy Disability (PND) Stage Based on Worst Post-Baseline Score | Baseline Stage 1, Post-baseline Stage 4 | 0 Participants |
| All Patients | Number of Participants in Each Polyneuropathy Disability (PND) Stage Based on Worst Post-Baseline Score | Baseline Stage 2, Post-baseline Stage 0 | 0 Participants |
| All Patients | Number of Participants in Each Polyneuropathy Disability (PND) Stage Based on Worst Post-Baseline Score | Baseline Stage 2, Post-baseline Stage 1 | 1 Participants |
| All Patients | Number of Participants in Each Polyneuropathy Disability (PND) Stage Based on Worst Post-Baseline Score | Baseline Stage 2, Post-baseline Stage 2 | 0 Participants |
| All Patients | Number of Participants in Each Polyneuropathy Disability (PND) Stage Based on Worst Post-Baseline Score | Baseline Stage 2, Post-baseline Stage 3A/B | 0 Participants |
| All Patients | Number of Participants in Each Polyneuropathy Disability (PND) Stage Based on Worst Post-Baseline Score | Baseline Stage 2, Post-baseline Stage 4 | 0 Participants |
| All Patients | Number of Participants in Each Polyneuropathy Disability (PND) Stage Based on Worst Post-Baseline Score | Baseline Stage 3A/B, Post-baseline Stage 0 | 0 Participants |
| All Patients | Number of Participants in Each Polyneuropathy Disability (PND) Stage Based on Worst Post-Baseline Score | Baseline Stage 4, Post-baseline Stage 0 | 0 Participants |
| All Patients | Number of Participants in Each Polyneuropathy Disability (PND) Stage Based on Worst Post-Baseline Score | Baseline Stage 4, Post-baseline Stage 1 | 0 Participants |
| All Patients | Number of Participants in Each Polyneuropathy Disability (PND) Stage Based on Worst Post-Baseline Score | Baseline Stage 4, Post-baseline Stage 2 | 0 Participants |
Secondary
Percentage Change From Baseline in Serum TTR Over 18 Months
A negative percentage change from baseline indicates a reduction in serum TTR level.
Time frame: Weeks 3, 7, 12, 18, 24, 26 (Month 6), 39 (Month 9), 52 (Month 12), 57, 78 (Month 18)
Population: Safety analysis set: All participants who received at least a single dose of study drug and for whom data were collected at each time point. Data collection was limited due to the discontinuation of the drug treatment early in the study as per protocol amendment.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| All Patients | Percentage Change From Baseline in Serum TTR Over 18 Months | Week 3 | -75.1 percentage change from baseline in TTR | Standard Deviation 18.79 |
| All Patients | Percentage Change From Baseline in Serum TTR Over 18 Months | Week 7 | -79.0 percentage change from baseline in TTR | Standard Deviation 15.46 |
| All Patients | Percentage Change From Baseline in Serum TTR Over 18 Months | Week 12 | -73.0 percentage change from baseline in TTR | Standard Deviation 18.61 |
| All Patients | Percentage Change From Baseline in Serum TTR Over 18 Months | Week 18 | -73.5 percentage change from baseline in TTR | Standard Deviation 14.3 |
| All Patients | Percentage Change From Baseline in Serum TTR Over 18 Months | Week 24 | -73.4 percentage change from baseline in TTR | Standard Deviation 14.32 |
| All Patients | Percentage Change From Baseline in Serum TTR Over 18 Months | Week 26 (Month 6) | -72.0 percentage change from baseline in TTR | Standard Deviation 18.39 |