Amyloidosis, Hereditary, Transthyretin Amyloidosis
Conditions
Brief summary
The purpose of this study is to evaluate the efficacy and safety of vutrisiran (ALN-TTRSC02) in participants with hereditary transthyretin amyloidosis (hATTR amyloidosis). Participants will receive vutrisiran subcutaneous (SC) injection once every 3 months (q3M) or the reference comparator patisiran intravenous (IV) injection once every 3 weeks (q3w) during the 18 month Treatment Period. This study will use the placebo arm of the APOLLO study (NCT01960348) as an external comparator for the primary and most other efficacy endpoints during the 18 Month Treatment Period. Following the 18 Month Treatment Period, all participants will be randomized to receive vutrisiran 50 mg SC injection once every 6 months (q6M) or vutrisiran 25 mg q3M in the Randomized Treatment Extension (RTE) Period. Upon implementation of Amendment 6, participants receiving vutrisiran SC 50 mg q6M will transition to vutrisiran SC 25 mg q3M at their next scheduled dosing.
Interventions
DRUGPatisiran
Patisiran will be administered by IV infusion.
DRUGVutrisiran
Vutrisiran will be administered by SC injection.
Sponsors
Alnylam Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
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); * Has a diagnosis of hATTR amyloidosis with transthyretin (TTR) mutation; * Has adequate neurologic impairment score (NIS); * Has adequate polyneuropathy disability (PND) score; * Has adequate Karnofsky Performance Status (KPS).
Exclusion criteria
* Had a prior liver transplant or is likely to undergo liver transplantation during the study; * Has known other (non-hATTR) forms of amyloidosis or leptomeningeal amyloidosis; * Has New York Heart Association heart failure classification \>2; * Clinically significant liver function test abnormalities; * Has known human immunodeficiency virus (HIV), hepatitis C virus (HCV) or hepatitis B virus (HBV) infection; * Received an experimental drug within 30 days of dosing; * Received prior TTR-lowering treatment; * Has other known causes of neuropathy.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in the Modified Neurologic Impairment Score +7 (mNIS+7) at Month 9 Between the Vutrisiran Group (HELIOS-A) and the External Placebo Comparator Group [APOLLO (NCT01960348)] | Baseline, Month 9 | 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 mNIS+7 is scored from 0 (no impairment) to 304 points (maximum impairment). A higher score indicates a worse outcome. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in the Timed 10-Meter Walk Test (10-MWT) at Month 9 Between the Vutrisiran Group (HELIOS-A) and the External Placebo Comparator Group [APOLLO (NCT01960348)] | Baseline, Month 9 | The 10-MWT is a measure of ambulatory ability and measures the time (in seconds) that it takes a participant to walk 10 meters (gait speed). An increase in gait speed from baseline represents improvement, and a decrease from baseline represents worsening. |
| Change From Baseline in the Modified Neurologic Impairment Score +7 (mNIS+7) at Month 18 Between the Vutrisiran Group (HELIOS-A) and the External Placebo Comparator Group [APOLLO (NCT01960348)] | Baseline, Month 18 | The mNIS+7 is a composite score that quantifies motor, sensory, and autonomic neurologic impairment due to injury of large and small nerves. The mNIS+7 is scored from 0 (no impairment) to 304 points (maximum impairment). A higher score indicates a worse outcome. |
| Change From Baseline in Norfolk QoL-DN Total Score at Month 18 Between the Vutrisiran Group (HELIOS-A) and the External Placebo Comparator Group [APOLLO (NCT01960348)] | Baseline, Month 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 total score ranges from -4 (best possible quality of life) to 136 points (worst possible quality of life). A higher score indicates a worse outcome. |
| Change From Baseline in Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QoL-DN) Total Score at Month 9 Between the Vutrisiran Group (HELIOS-A) and the External Placebo Comparator Group [APOLLO (NCT01960348)] | Baseline, Month 9 | 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 total score ranges from -4 (best possible quality of life) to 136 points (worst possible quality of life). A higher score indicates a worse outcome. |
| Change From Baseline in the Modified Body Mass Index (mBMI) at Month 18 Between the Vutrisiran Group (HELIOS-A) and the External Placebo Comparator Group [APOLLO (NCT01960348)] | Baseline, Month 18 | The mBMI, which is a measure of nutritional status, is calculated as the product of body mass index (BMI) (weight in kilograms divided by the square of height in meters) and serum albumin (g/L) to reflect fluid balance, such as fluid accumulation or dehydration. A negative change from baseline indicates a better outcome. |
| Change From Baseline in the Rasch-Built Overall Disability Scale (R-ODS) at Month 18 Between the Vutrisiran Group (HELIOS-A) and the External Placebo Comparator Group [APOLLO (NCT01960348)] | Baseline, Month 18 | The R-ODS is a patient-reported measure of level of disability on a scale of 0-48, with 0 being the worst and 48 the best (no limitations); scores are based on activities of daily living and social participation. An increase in R-ODS from baseline suggests improvement in disability, and a decrease from baseline suggests worsening of disability. |
| Percent Reduction in Serum Transthyretin (TTR) Levels Through Month 18 Between the Vutrisiran Group (HELIOS-A) and the Patisiran Group (HELIOS-A) | Up to Month 18 | Serum TTR was assessed at multiple timepoints up to Month 18. |
| Change From Baseline in the 10-MWT at Month 18 Between the Vutrisiran Group (HELIOS-A) and the External Placebo Comparator Group [APOLLO (NCT01960348)] | Baseline, Month 18 | The 10-MWT is a measure of ambulatory ability and measures the time (in seconds) that it takes a participant to walk 10 meters (gait speed). An increase in gait speed from baseline represents improvement, and a decrease from baseline represents worsening. |
Countries
Argentina, Australia, Belgium, Brazil, Bulgaria, Canada, Cyprus, France, Germany, Greece, Italy, Japan, Malaysia, Mexico, Netherlands, Portugal, South Korea, Spain, Sweden, Taiwan, United Kingdom, United States
Participant flow
Recruitment details
Participants with hATTR amyloidosis were enrolled and treated at 57 sites in Argentina, Australia, Belgium, Brazil, Bulgaria, Canada, Cyprus, France, Germany, Greece, Italy, Japan, Korea, Malaysia, Mexico, Netherlands, Portugal, Spain, Sweden, Taiwan, United Kingdom and United States. Data is reported for the 9-Month primary analysis period.
Pre-assignment details
This study will use the placebo arm of the APOLLO study (NCT01960348) as an external comparator for the primary and most other efficacy endpoints (N=77).
Participants by arm
| Arm | Count |
|---|---|
| External Placebo Comparator (APOLLO) Participants in the APOLLO study (NCT01960348) who received at least 1 dose of placebo. | 77 |
| Vutrisiran + Vutrisiran (HELIOS-A) Participants will receive vutrisiran 25 mg SC injection q3M for 18 months during the Treatment Period followed by vutrisiran SC injection q6M or q3M during the RTE Period. | 122 |
| Patisiran + Vutrisiran (HELIOS-A) Participants will receive patisiran 0.3 mg/kg IV infusion q3w for 18 months during the Treatment Period followed by vutrisiran SC injection q6M or q3M during the RTE Period. | 42 |
| Total | 241 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Treatment Period | Death | 2 | 3 |
| Treatment Period | Lost to Follow-up | 1 | 0 |
| Treatment Period | Physician Decision | 0 | 1 |
| Treatment Period | Remained in this Period at Time of Data Cut | 119 | 38 |
Baseline characteristics
| Characteristic | Patisiran + Vutrisiran (HELIOS-A) | Total | External Placebo Comparator (APOLLO) | Vutrisiran + Vutrisiran (HELIOS-A) |
|---|---|---|---|---|
| Age, Continuous | 58.0 years STANDARD_DEVIATION 10.5 | 62.2 years STANDARD_DEVIATION 10.76 | 62.2 years STANDARD_DEVIATION 10.76 | 57.8 years STANDARD_DEVIATION 13.2 |
| Modified Neuropathy Impairment Score +7 (mNIS+7) | 57.69 score on a scale STANDARD_DEVIATION 33.71 | 59.82 score on a scale STANDARD_DEVIATION 35.34 | 74.61 score on a scale STANDARD_DEVIATION 37.041 | 60.55 score on a scale STANDARD_DEVIATION 35.99 |
| Race/Ethnicity, Customized Asian | 8 Participants | 25 Participants | 25 Participants | 21 Participants |
| Race/Ethnicity, Customized Black or African American | 4 Participants | 8 Participants | 0 Participants | 4 Participants |
| Race/Ethnicity, Customized Multiple | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Other | 1 Participants | 11 Participants | 0 Participants | 10 Participants |
| Race/Ethnicity, Customized Unknown | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Unknown or Not Reported | — | 1 Participants | 1 Participants | — |
| Race/Ethnicity, Customized White | 29 Participants | 50 Participants | 0 Participants | 86 Participants |
| Sex: Female, Male Female | 15 Participants | 19 Participants | 19 Participants | 43 Participants |
| Sex: Female, Male Male | 27 Participants | 106 Participants | 58 Participants | 79 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 2 / 122 | 3 / 42 |
| other Total, other adverse events | 78 / 122 | 31 / 42 |
| serious Total, serious adverse events | 21 / 122 | 17 / 42 |
Outcome results
Primary
Change From Baseline in the Modified Neurologic Impairment Score +7 (mNIS+7) at Month 9 Between the Vutrisiran Group (HELIOS-A) and the External Placebo Comparator Group [APOLLO (NCT01960348)]
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 mNIS+7 is scored from 0 (no impairment) to 304 points (maximum impairment). A higher score indicates a worse outcome.
Time frame: Baseline, Month 9
Population: Modified Intent-to-Treat (mITT) Population: All randomized participants who received any amount of study drug. Participants were analyzed according to the treatment to which they were randomized.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| External Placebo Comparator (APOLLO) | Change From Baseline in the Modified Neurologic Impairment Score +7 (mNIS+7) at Month 9 Between the Vutrisiran Group (HELIOS-A) and the External Placebo Comparator Group [APOLLO (NCT01960348)] | 14.76 score on a scale | Standard Error 2 |
| Vutrisiran + Vutrisiran (HELIOS-A) | Change From Baseline in the Modified Neurologic Impairment Score +7 (mNIS+7) at Month 9 Between the Vutrisiran Group (HELIOS-A) and the External Placebo Comparator Group [APOLLO (NCT01960348)] | -2.24 score on a scale | Standard Error 1.43 |
Comparison: Multiple imputation estimates and p-value derived per combining least squares (LS) estimates per Rubin's rules based on 100 datasets where missing Month 9 values were imputed using a regression procedure including select baseline variables. LS estimates derived from analysis of covariance model, controlling for categorical factors (treatment, genotype, age of disease onset) and continuous covariate (baseline value).p-value: <1e-795% CI: [-21.78, -12.22]ANCOVA with Multiple Imputation
Secondary
Change From Baseline in Norfolk QoL-DN Total Score at Month 18 Between the Vutrisiran Group (HELIOS-A) and the External Placebo Comparator Group [APOLLO (NCT01960348)]
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 total score ranges from -4 (best possible quality of life) to 136 points (worst possible quality of life). A higher score indicates a worse outcome.
Time frame: Baseline, Month 18
Secondary
Change From Baseline in Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QoL-DN) Total Score at Month 9 Between the Vutrisiran Group (HELIOS-A) and the External Placebo Comparator Group [APOLLO (NCT01960348)]
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 total score ranges from -4 (best possible quality of life) to 136 points (worst possible quality of life). A higher score indicates a worse outcome.
Time frame: Baseline, Month 9
Population: Modified Intent-to-Treat (mITT) Population: All randomized participants who received any amount of study drug. Participants were analyzed according to the treatment to which they were randomized.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| External Placebo Comparator (APOLLO) | Change From Baseline in Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QoL-DN) Total Score at Month 9 Between the Vutrisiran Group (HELIOS-A) and the External Placebo Comparator Group [APOLLO (NCT01960348)] | 12.9 score on a scale | Standard Error 2.2 |
| Vutrisiran + Vutrisiran (HELIOS-A) | Change From Baseline in Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QoL-DN) Total Score at Month 9 Between the Vutrisiran Group (HELIOS-A) and the External Placebo Comparator Group [APOLLO (NCT01960348)] | -3.3 score on a scale | Standard Error 1.7 |
Comparison: Multiple imputation estimates and p-value derived per combining least squares (LS) estimates per Rubin's rules based on 100 datasets where missing Month 9 values were imputed using a regression procedure including select baseline variables. LS estimates derived from analysis of covariance model, controlling for categorical factors (treatment, genotype, age of disease onset baseline NIS) and continuous covariate (baseline value).p-value: <1e-795% CI: [-21.7, -10.8]ANCOVA with Multiple Imputation
Secondary
Change From Baseline in the 10-MWT at Month 18 Between the Vutrisiran Group (HELIOS-A) and the External Placebo Comparator Group [APOLLO (NCT01960348)]
The 10-MWT is a measure of ambulatory ability and measures the time (in seconds) that it takes a participant to walk 10 meters (gait speed). An increase in gait speed from baseline represents improvement, and a decrease from baseline represents worsening.
Time frame: Baseline, Month 18
Secondary
Change From Baseline in the Modified Body Mass Index (mBMI) at Month 18 Between the Vutrisiran Group (HELIOS-A) and the External Placebo Comparator Group [APOLLO (NCT01960348)]
The mBMI, which is a measure of nutritional status, is calculated as the product of body mass index (BMI) (weight in kilograms divided by the square of height in meters) and serum albumin (g/L) to reflect fluid balance, such as fluid accumulation or dehydration. A negative change from baseline indicates a better outcome.
Time frame: Baseline, Month 18
Secondary
Change From Baseline in the Modified Neurologic Impairment Score +7 (mNIS+7) at Month 18 Between the Vutrisiran Group (HELIOS-A) and the External Placebo Comparator Group [APOLLO (NCT01960348)]
The mNIS+7 is a composite score that quantifies motor, sensory, and autonomic neurologic impairment due to injury of large and small nerves. The mNIS+7 is scored from 0 (no impairment) to 304 points (maximum impairment). A higher score indicates a worse outcome.
Time frame: Baseline, Month 18
Secondary
Change From Baseline in the Rasch-Built Overall Disability Scale (R-ODS) at Month 18 Between the Vutrisiran Group (HELIOS-A) and the External Placebo Comparator Group [APOLLO (NCT01960348)]
The R-ODS is a patient-reported measure of level of disability on a scale of 0-48, with 0 being the worst and 48 the best (no limitations); scores are based on activities of daily living and social participation. An increase in R-ODS from baseline suggests improvement in disability, and a decrease from baseline suggests worsening of disability.
Time frame: Baseline, Month 18
Secondary
Change From Baseline in the Timed 10-Meter Walk Test (10-MWT) at Month 9 Between the Vutrisiran Group (HELIOS-A) and the External Placebo Comparator Group [APOLLO (NCT01960348)]
The 10-MWT is a measure of ambulatory ability and measures the time (in seconds) that it takes a participant to walk 10 meters (gait speed). An increase in gait speed from baseline represents improvement, and a decrease from baseline represents worsening.
Time frame: Baseline, Month 9
Population: Modified Intent-to-Treat (mITT) Population: All randomized participants who received any amount of study drug. Participants were analyzed according to the treatment to which they were randomized.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| External Placebo Comparator (APOLLO) | Change From Baseline in the Timed 10-Meter Walk Test (10-MWT) at Month 9 Between the Vutrisiran Group (HELIOS-A) and the External Placebo Comparator Group [APOLLO (NCT01960348)] | -0.133 m/sec | Standard Error 0.025 |
| Vutrisiran + Vutrisiran (HELIOS-A) | Change From Baseline in the Timed 10-Meter Walk Test (10-MWT) at Month 9 Between the Vutrisiran Group (HELIOS-A) and the External Placebo Comparator Group [APOLLO (NCT01960348)] | -0.001 m/sec | Standard Error 0.019 |
Comparison: Multiple imputation estimates and p-value derived per combining least squares (LS) estimates per Rubin's rules based on 100 datasets where missing Month 9 values were imputed using a regression procedure including select baseline variables. LS estimates derived from analysis of covariance model, controlling for categorical factors (treatment, genotype, age of disease onset, baseline NIS) and continuous covariate (baseline value).p-value: <1e-795% CI: [0.07, 0.193]ANCOVA with Multiple Imputation
Secondary
Percent Reduction in Serum Transthyretin (TTR) Levels Through Month 18 Between the Vutrisiran Group (HELIOS-A) and the Patisiran Group (HELIOS-A)
Serum TTR was assessed at multiple timepoints up to Month 18.
Time frame: Up to Month 18