Amyloid Neuropathies, Amyloid Neuropathies, Familial, Amyloidosis, Hereditary, Amyloidosis, Hereditary, Transthyretin-Related, Familial Amyloid Polyneuropathies, TTR-mediated Amyloidosis
Conditions
Keywords
RNAi therapeutic, FAP, Familial Amyloid Polyneuropathy, TTR, Transthyretin, Amyloidosis
Brief summary
The purpose of this study is to evaluate the safety and efficacy of patisiran (ALN-TTR02) in patients with transthyretin (TTR) mediated amyloidosis. An open-label, single-arm, long-term follow-up extension study NCT02510261 (ALN-TTR02-006) was initiated to provide participants who completed this study with continued patisiran-LNP (lipid nanoparticle) treatment.
Interventions
administered by intravenous (IV) infusion
DRUGSterile Normal Saline (0.9% NaCl)
administered by intravenous (IV) infusion
Sponsors
Alnylam Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
* Male or female of 18 to 85 years of age (inclusive); * Have a diagnosis of FAP * Neuropathy Impairment Score requirement of 5-130 * Meet Karnofsky performance status requirements * Have adequate complete blood counts and liver function tests * Have adequate cardiac function * Have negative serology for hepatitis B virus (HBV) and hepatitis C virus (HCV)
Exclusion criteria
* Had a prior liver transplant or is planned to undergo liver transplant during the study period; * Has untreated hypo- or hyperthyroidism; * Has known human immunodeficiency virus (HIV) infection; * Had a malignancy within 2 years, except for basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix that has been successfully treated; * Recently received an investigational agent or device * Is currently taking diflunisal, tafamidis, doxycycline, or tauroursodeoxycholic acid
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Modified Neuropathy Impairment Score +7 (mNIS+7) | 18mo | The difference between the patisiran (ALN-TTR02) and placebo groups in the change from baseline in mNIS+7 at 18 months. The mNIS+7 is a composite score that quantitates motor, sensory, and autonomic neurologic impairment due to injury of large and small nerves. The minimum and maximum values are 0 and 304, respectively. A higher score indicates a worse outcome. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Neurological Impairment Score-Weakness (NIS-W) Score | 18mo | The difference between the patisiran (ALN-TTR02) and placebo groups in the change from baseline in NIS-W at 18 months. NIS-W is a measure of motor strength, comprised of cranial nerve and both upper and lower limb motor assessments. The minimum and maximum values are 0 and 192, respectively. A higher score indicates a worse outcome. |
| Rasch-built Overall Disability Scale (R-ODS) Score | 18mo | The difference between the patisiran (ALN-TTR02) and placebo groups in the change from baseline in R-ODS score at 18 months. The R-ODS is comprised of a 24-item linearly weighted scale that specifically captures activity and social participation limitations in patients. The minimum and maximum values are 0 and 48, respectively. A higher score indicates a better outcome. |
| Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QoL-DN) Questionnaire | 18mo | The difference between the patisiran (ALN-TTR02) and placebo groups in the change from baseline in Norfolk QoL-DN at 18 months. 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. |
| Modified Body Mass Index (mBMI) | 18mo | The difference between the patisiran (ALN-TTR02) and placebo groups in the change from baseline in mBMI at 18 months. The nutritional status of patients was evaluated using the mBMI; calculated as the product of BMI (weight in kilograms divided by the square of height in meters) and serum albumin (g/L). |
| Autonomic Symptoms Questionnaire (Composite Autonomic Symptom Score [COMPASS 31]) | 18mo | The difference between the patisiran (ALN-TTR02) and placebo groups in the change from baseline in COMPASS 31 at 18 months. The COMPASS 31 is a measure of autonomic neuropathy symptoms. The questions evaluated 6 autonomic domains (orthostatic intolerance, vasomotor, secretomotor, gastrointestinal, bladder, and pupillomotor). The minimum and maximum values are 0 and 100, respectively. A higher score indicates a worse outcome. |
| Timed 10-meter Walk Test (10-MWT, Gait Speed) | 18mo | The difference between the patisiran (ALN-TTR02) and placebo groups in the change from baseline in 10-MWT at 18 months. Ability to ambulate (gait speed) was assessed through the 10-meter walk test (10-MWT). The walk had to be completed without assistance from another person; ambulatory aids such as canes and walkers were permitted. |
Countries
Argentina, Australia, Brazil, Bulgaria, Canada, Cyprus, France, Germany, Italy, Japan, Malaysia, Mexico, Netherlands, Portugal, South Korea, Spain, Sweden, Taiwan, Turkey (Türkiye), United Kingdom, United States
Participant flow
Recruitment details
A total of 225 patients with hereditary transthyretin (hATTR) amyloidosis were enrolled and randomized in the study.
Participants by arm
| Arm | Count |
|---|---|
| Patisiran (ALN-TTR02) All patients who received at least 1 dose of patisiran (ALN-TTR02) | 148 |
| Placebo All patients who received at least 1 dose of placebo | 77 |
| Total | 225 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse event, not serious | 2 | 2 |
| Overall Study | Adverse event, serious fatal | 6 | 5 |
| Overall Study | Adverse event, serious non-fatal | 0 | 3 |
| Overall Study | Physician Decision | 0 | 1 |
| Overall Study | Protocol Violation | 1 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 11 |
Baseline characteristics
| Characteristic | Patisiran (ALN-TTR02) | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 59.6 years STANDARD_DEVIATION 11.96 | 62.2 years STANDARD_DEVIATION 10.76 | 60.5 years STANDARD_DEVIATION 11.61 |
| Age, Customized 65-74 years | 53 Participants | 24 Participants | 77 Participants |
| Age, Customized <65 years | 86 Participants | 44 Participants | 130 Participants |
| Age, Customized ≥75 years | 9 Participants | 9 Participants | 18 Participants |
| Baseline mNIS+7 | 80.93 Points STANDARD_DEVIATION 41.507 | 74.61 Points STANDARD_DEVIATION 37.041 | 78.77 Points STANDARD_DEVIATION 40.064 |
| Baseline NIS NIS <50 | 62 Participants | 35 Participants | 97 Participants |
| Baseline NIS NIS ≥50 | 86 Participants | 42 Participants | 128 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 17 Participants | 11 Participants | 28 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 130 Participants | 65 Participants | 195 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 2 Participants |
| Genotype Class All other mutations (including late onset V30M) | 135 Participants | 67 Participants | 202 Participants |
| Genotype Class Early onset V30M (<50 years of age at onset) | 13 Participants | 10 Participants | 23 Participants |
| Previous Tetramer Stabilizer Use No | 70 Participants | 36 Participants | 106 Participants |
| Previous Tetramer Stabilizer Use Yes | 78 Participants | 41 Participants | 119 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 27 Participants | 25 Participants | 52 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants | 1 Participants | 5 Participants |
| Race (NIH/OMB) More than one race | 2 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 1 Participants | 3 Participants |
| Race (NIH/OMB) White | 113 Participants | 50 Participants | 163 Participants |
| Sex: Female, Male Female | 39 Participants | 19 Participants | 58 Participants |
| Sex: Female, Male Male | 109 Participants | 58 Participants | 167 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 7 / 148 | 6 / 77 |
| other Total, other adverse events | 143 / 148 | 75 / 77 |
| serious Total, serious adverse events | 54 / 148 | 31 / 77 |
Outcome results
Primary
Modified Neuropathy Impairment Score +7 (mNIS+7)
The difference between the patisiran (ALN-TTR02) and placebo groups in the change from baseline in mNIS+7 at 18 months. The mNIS+7 is a composite score that quantitates motor, sensory, and autonomic neurologic impairment due to injury of large and small nerves. The minimum and maximum values are 0 and 304, respectively. A higher score indicates a worse outcome.
Time frame: 18mo
Population: Per protocol (PP) population: All randomized participants who received at least 1 dose of patisiran-LNP or placebo, completed baseline and the 18-month mNIS+7 assessments, and did not experience any major protocol deviations that may have impacted the efficacy results.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Patisiran (ALN-TTR02) | Modified Neuropathy Impairment Score +7 (mNIS+7) | -6.03 score on a scale | Standard Error 1.739 |
| Placebo | Modified Neuropathy Impairment Score +7 (mNIS+7) | 27.96 score on a scale | Standard Error 2.602 |
Comparison: In the mixed-effect model repeated measures (MMRM) model, the outcome variable is change from baseline in mNIS+7. The model includes baseline mNIS+7 score as covariate and fixed effect terms including treatment group, visit, treatment-by-visit interaction, genotype, age at hATTR symptom onset, previous tetramer stabilizer use and region.p-value: <1e-795% CI: [-39.86, -28.13]Mixed-effect Model Repeated Measures
Secondary
Autonomic Symptoms Questionnaire (Composite Autonomic Symptom Score [COMPASS 31])
The difference between the patisiran (ALN-TTR02) and placebo groups in the change from baseline in COMPASS 31 at 18 months. The COMPASS 31 is a measure of autonomic neuropathy symptoms. The questions evaluated 6 autonomic domains (orthostatic intolerance, vasomotor, secretomotor, gastrointestinal, bladder, and pupillomotor). The minimum and maximum values are 0 and 100, respectively. A higher score indicates a worse outcome.
Time frame: 18mo
Population: Per protocol (PP) population: All randomized participants who received at least 1 dose of patisiran-LNP or placebo, completed baseline and the 18-month COMPASS 31 assessments, and did not experience any major protocol deviations that may have impacted the efficacy results.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Patisiran (ALN-TTR02) | Autonomic Symptoms Questionnaire (Composite Autonomic Symptom Score [COMPASS 31]) | -5.29 score on a scale | Standard Error 1.3 |
| Placebo | Autonomic Symptoms Questionnaire (Composite Autonomic Symptom Score [COMPASS 31]) | 2.24 score on a scale | Standard Error 1.94 |
Comparison: In the mixed-effect model repeated measures (MMRM) model, the outcome variable is change from baseline in COMPASS-31 total score. The model includes baseline COMPASS-31 score as covariate and fixed effect terms including treatment group, visit, treatment-by-visit interaction, baseline NIS, genotype, age at hATTR symptom onset, previous tetramer stabilizer use and region.p-value: 0.000895% CI: [-11.89, -3.16]Mixed-effect Model Repeated Measures
Secondary
Modified Body Mass Index (mBMI)
The difference between the patisiran (ALN-TTR02) and placebo groups in the change from baseline in mBMI at 18 months. The nutritional status of patients was evaluated using the mBMI; calculated as the product of BMI (weight in kilograms divided by the square of height in meters) and serum albumin (g/L).
Time frame: 18mo
Population: Per protocol (PP) population: All randomized participants who received at least 1 dose of patisiran-LNP or placebo, completed baseline and the 18-month mBMI assessments and did not experience any major protocol deviations that may have impacted the results..
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Patisiran (ALN-TTR02) | Modified Body Mass Index (mBMI) | -3.7 kg/m^2 × albumin g/L | Standard Error 9.57 |
| Placebo | Modified Body Mass Index (mBMI) | -119.4 kg/m^2 × albumin g/L | Standard Error 14.51 |
Comparison: In the mixed-effect model repeated measures (MMRM) model, the outcome variable is change from baseline in mBMI. The model includes baseline mBMI as covariate and fixed effect terms including treatment group, visit, treatment-by-visit interaction, baseline NIS, genotype, age at hATTR symptom onset, previous tetramer stabilizer use and region.p-value: <1e-795% CI: [82.4, 149]Mixed-effect Model Repeated Measures
Secondary
Neurological Impairment Score-Weakness (NIS-W) Score
The difference between the patisiran (ALN-TTR02) and placebo groups in the change from baseline in NIS-W at 18 months. NIS-W is a measure of motor strength, comprised of cranial nerve and both upper and lower limb motor assessments. The minimum and maximum values are 0 and 192, respectively. A higher score indicates a worse outcome.
Time frame: 18mo
Population: Per protocol (PP) population: All randomized participants who received at least 1 dose of patisiran-LNP or placebo, completed baseline and the 18-month NIS-W assessments, and did not experience any major protocol deviations that may have impacted the efficacy results.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Patisiran (ALN-TTR02) | Neurological Impairment Score-Weakness (NIS-W) Score | 0.05 score on a scale | Standard Error 1.306 |
| Placebo | Neurological Impairment Score-Weakness (NIS-W) Score | 17.93 score on a scale | Standard Error 1.959 |
Comparison: In the mixed-effect model repeated measures (MMRM) model, the outcome variable is change from baseline in NIS-W. The model includes baseline NIS-W score as covariate and fixed effect terms including treatment group, visit, treatment-by-visit interaction, genotype, age at hATTR symptom onset, previous tetramer stabilizer use and region.p-value: <1e-795% CI: [-22.32, -13.43]Mixed-effect Model Repeated Measures
Secondary
Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QoL-DN) Questionnaire
The difference between the patisiran (ALN-TTR02) and placebo groups in the change from baseline in Norfolk QoL-DN at 18 months. 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: 18mo
Population: Per protocol (PP) population: All randomized participants who received at least 1 dose of patisiran-LNP or placebo, completed baseline and the 18-month Norfolk QoL-DN assessments, and did not experience any major protocol deviations that may have impacted the efficacy results.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Patisiran (ALN-TTR02) | Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QoL-DN) Questionnaire | -6.7 score on a scale | Standard Error 1.77 |
| Placebo | Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QoL-DN) Questionnaire | 14.4 score on a scale | Standard Error 2.73 |
Comparison: In the mixed-effect model repeated measures (MMRM) model, the outcome variable is change from baseline in Norfolk QOL-DN total score. The model includes baseline Norfolk QOL-DN score as covariate and fixed effect terms including treatment group, visit, treatment-by-visit interaction, baseline NIS, genotype, age at hATTR symptom onset, previous tetramer stabilizer use and region.p-value: <1e-795% CI: [-27.2, -15]Mixed-effect Model Repeated Measures
Secondary
Rasch-built Overall Disability Scale (R-ODS) Score
The difference between the patisiran (ALN-TTR02) and placebo groups in the change from baseline in R-ODS score at 18 months. The R-ODS is comprised of a 24-item linearly weighted scale that specifically captures activity and social participation limitations in patients. The minimum and maximum values are 0 and 48, respectively. A higher score indicates a better outcome.
Time frame: 18mo
Population: Per protocol (PP) population: All randomized participants who received at least 1 dose of patisiran-LNP or placebo, completed baseline and either the 18-month R-ODS assessments, and did not experience any major protocol deviations that may have impacted the efficacy results.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Patisiran (ALN-TTR02) | Rasch-built Overall Disability Scale (R-ODS) Score | 0.0 score on a scale | Standard Error 0.59 |
| Placebo | Rasch-built Overall Disability Scale (R-ODS) Score | -8.9 score on a scale | Standard Error 0.88 |
Comparison: In the mixed-effect model repeated measures (MMRM) model, the outcome variable is change from baseline in R-ODS value. The model includes baseline R-ODS score as covariate and fixed effect terms including treatment group, visit, treatment-by-visit interaction, baseline NIS, genotype, age at hATTR symptom onset, previous tetramer stabilizer use and region.p-value: <1e-795% CI: [7, 10.9]Mixed-effect Model Repeated Measures
Secondary
Timed 10-meter Walk Test (10-MWT, Gait Speed)
The difference between the patisiran (ALN-TTR02) and placebo groups in the change from baseline in 10-MWT at 18 months. Ability to ambulate (gait speed) was assessed through the 10-meter walk test (10-MWT). The walk had to be completed without assistance from another person; ambulatory aids such as canes and walkers were permitted.
Time frame: 18mo
Population: Per protocol (PP) population: All randomized participants who received at least 1 dose of patisiran-LNP or placebo, completed baseline and the 18-month 10-MWT assessments, and did not experience any major protocol deviations that may have impacted the efficacy results.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Patisiran (ALN-TTR02) | Timed 10-meter Walk Test (10-MWT, Gait Speed) | 0.077 m/sec | Standard Error 0.0242 |
| Placebo | Timed 10-meter Walk Test (10-MWT, Gait Speed) | -0.235 m/sec | Standard Error 0.0358 |
Comparison: In the mixed-effect model repeated measures (MMRM) model, the outcome variable is change from baseline in 10-meter walk test result. The model includes baseline 10-meter walk test result as covariate and fixed effect terms including treatment group, visit, treatment-by-visit interaction, baseline NIS, genotype, age at hATTR symptom onset, previous tetramer stabilizer use and region.p-value: <1e-795% CI: [0.23, 0.393]Mixed-effect Model Repeated Measures