Transthyretin Amyloidosis (ATTR) With Cardiomyopathy
Conditions
Keywords
RNAi therapeutic, Transthyretin, TTR, Amyloidosis, Cardiomyopathy, ATTR
Brief summary
The purpose of this study is to evaluate the efficacy and safety of patisiran in participants with ATTR amyloidosis with cardiomyopathy.
Interventions
DRUGPlacebo
Normal saline (0.9% NaCl) matching volume of patisiran doses will be administered intravenously.
DRUGPatisiran
Patisiran will be administered by intravenous (IV) infusion.
Sponsors
Alnylam Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
* Documented diagnosis of ATTR amyloidosis with cardiomyopathy, classified as either hereditary ATTR amyloidosis with cardiomyopathy or wild-type ATTR amyloidosis with cardiomyopathy * Medical history of heart failure with at least 1 prior hospitalization for heart failure, or current clinical evidence (signs and symptoms of heart failure) * Clinically stable with no cardiovascular related hospitalizations within 6 weeks of study start * Has never taken tafamidis before (tafamidis naïve) or currently on tafamidis for ≥6 months with evidence of disease progression while on tafamidis treatment * Able to complete ≥150 m on the 6-minute walk test * Screening N-terminal pro B-type natriuretic peptide (NT-proBNP), a blood marker of heart failure severity, \>300 ng/L and \<8500 ng/L; in participants with permanent or persistent atrial fibrillation, screening NT-proBNP\> 600 ng/L and \<8500 ng/L
Exclusion criteria
* Known primary amyloidosis (AL) or leptomeningeal amyloidosis. * Received prior TTR lowering treatment * New York Heart Association heart failure classification of III and at high risk * New York Heart Association heart failure classification of IV * Neuropathy requiring cane or stick to walk, or is wheelchair bound * Estimated glomerular filtration rate (eGFR) \<30 mL/min/1.73m\^2 * Abnormal liver function * Has hepatitis B, hepatitis C or human immunodeficiency virus (HIV) infection * Has non-amyloid disease that significantly affects ability to walk (e.g., severe chronic obstructive pulmonary disease, severe arthritis, or peripheral vascular disease affecting ambulation) * Prior or planned heart, liver, or other organ transplant * Other cardiomyopathy not related to ATTR amyloidosis
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline at Month 12 in Six-Minute Walk Test (6-MWT) | Baseline, Month 12 | Distance in meters walked in 6 minutes, longer distances indicate greater functional capacity. Missing 6MWT values due to non-COVID-19 death or inability to walk due to ATTR disease progression were imputed using the worst 10th percentile change observed in the DB period. Missing 6-MWT values due to other reasons are multiply imputed to create 100 complete datasets. The change from baseline is averaged across the 100 complete datasets. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline at Month 12 in Kansas City Cardiomyopathy Questionnaire Overall Summary (KCCQ-OS) Score | Baseline, Month 12 | The KCCQ is a 23-item self-administered questionnaire quantifying 6 domains (symptoms, physical function, quality of life, social limitation, self-efficacy, and symptom stability) and 2 summary scores (clinical and overall summary \[OS\]). Scores are transformed to a range of 0-100, in which higher scores reflect better health status. |
| Composite Endpoint of All-Cause Mortality, Frequency of Cardiovascular (CV) Events (CV Hospitalizations and Urgent Heart Failure [HF] Visits) and Change From Baseline in 6-MWT Analyzed by Win Ratio | Up to Month 12 | The composite endpoint was analyzed using the stratified win ratio method, stratified by baseline tafamidis use. This method combines all-cause mortality, frequency of CV events (CV hospitalizations and HF visits) and change from baseline in 6-MWT in a hierarchical fashion. This method makes within-stratum pairwise comparisons for all patisiran-placebo participant pairs in a sequential manner (first mortality, then CV events, then 6-MWT), with later steps evaluated only in the case of a tie on the prior step. Within each stratum, the win ratio is the total number of 'winners' divided by the total number of 'losers' in the active group. A win ratio \>1 represents a favorable outcome for patisiran. |
| Composite Endpoint of All-Cause Mortality and Frequency of All-Cause Hospitalizations and Urgent HF Visits in Participants Not on Tafamidis at Baseline | Up to Month 12 | The hazard rate of all-cause mortality and all-cause hospitalizations and urgent HF visits will be compared between treatment groups using an Andersen-Gill model. A hazard ratio \<1 represents a favorable outcome for patisiran. |
| Composite Endpoint of All-cause Mortality and Frequency of All-cause Hospitalizations and Urgent HF Visits in All Participants | Up to Month 12 | The hazard rate of all-cause mortality and all-cause hospitalizations and urgent HF visits was compared between treatment groups using a modified Andersen-Gill model. A hazard ratio \<1 represents a favorable outcome for patisiran. |
Countries
Argentina, Australia, Belgium, Brazil, Bulgaria, Chile, Czechia, Denmark, France, Hong Kong, Italy, Japan, Mexico, Netherlands, New Zealand, Poland, Portugal, South Korea, Sweden, Taiwan, United Kingdom, United States
Contacts
STUDY_DIRECTORMedical Director
Alnylam Pharmaceuticals
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo (DB)/Patisiran (OLE) Participants were administered placebo IV every 3 weeks during the 12-month double-blind (DB) treatment period. Participants will be administered patisiran 0.3 mg/kg IV every 3 weeks during the 36-month open label extension (OLE) period. | 178 |
| Patisiran (DB+OLE) Participants were administered patisiran 0.3 mg/kg intravenously (IV) every 3 weeks during the 12-month DB treatment period. Participants will be administered patisiran 0.3 mg/kg IV every 3 weeks during the 36-month OLE period. | 181 |
| Total | 359 |
Baseline characteristics
| Characteristic | Total | Patisiran (DB+OLE) | Placebo (DB)/Patisiran (OLE) |
|---|---|---|---|
| 6 Minute Walk Test (6MWT) | 362.0 meters | 356.8 meters | 367.7 meters |
| Age, Continuous | 74.8 years STANDARD_DEVIATION 7.2 | 75.3 years STANDARD_DEVIATION 6.5 | 74.2 years STANDARD_DEVIATION 7.8 |
| Race/Ethnicity, Customized Asian | 38 participants | 23 participants | 15 participants |
| Race/Ethnicity, Customized Black or African American | 31 participants | 16 participants | 15 participants |
| Race/Ethnicity, Customized Hispanic or Latino | 41 participants | 21 participants | 20 participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 303 participants | 153 participants | 150 participants |
| Race/Ethnicity, Customized Not Reported | 9 participants | 1 participants | 4 participants |
| Race/Ethnicity, Customized Other | 7 participants | 3 participants | 4 participants |
| Race/Ethnicity, Customized Unknown | 6 participants | 2 participants | 4 participants |
| Race/Ethnicity, Customized White | 278 participants | 138 participants | 140 participants |
| Sex: Female, Male Female | 38 Participants | 20 Participants | 18 Participants |
| Sex: Female, Male Male | 321 Participants | 161 Participants | 160 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 8 / 178 | 4 / 181 | 10 / 166 | 9 / 168 |
| other Total, other adverse events | 168 / 178 | 165 / 181 | 0 / 166 | 0 / 168 |
| serious Total, serious adverse events | 63 / 178 | 61 / 181 | 0 / 166 | 0 / 168 |
Outcome results
Primary
Change From Baseline at Month 12 in Six-Minute Walk Test (6-MWT)
Distance in meters walked in 6 minutes, longer distances indicate greater functional capacity. Missing 6MWT values due to non-COVID-19 death or inability to walk due to ATTR disease progression were imputed using the worst 10th percentile change observed in the DB period. Missing 6-MWT values due to other reasons are multiply imputed to create 100 complete datasets. The change from baseline is averaged across the 100 complete datasets.
Time frame: Baseline, Month 12
Population: Full Analysis Set: 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 (MEDIAN) |
|---|---|---|
| Placebo (DB)/Patisiran (OLE) | Change From Baseline at Month 12 in Six-Minute Walk Test (6-MWT) | -21.345 meters |
| Patisiran (DB+OLE) | Change From Baseline at Month 12 in Six-Minute Walk Test (6-MWT) | -8.150 meters |
p-value: 0.016295% CI: [0.693, 28.692]Wilcoxon Rank Sum Test
Secondary
Change From Baseline at Month 12 in Kansas City Cardiomyopathy Questionnaire Overall Summary (KCCQ-OS) Score
The KCCQ is a 23-item self-administered questionnaire quantifying 6 domains (symptoms, physical function, quality of life, social limitation, self-efficacy, and symptom stability) and 2 summary scores (clinical and overall summary \[OS\]). Scores are transformed to a range of 0-100, in which higher scores reflect better health status.
Time frame: Baseline, Month 12
Population: Full Analysis Set: All randomized participants who received any amount of study drug. Participants were analyzed according to the treatment to which they were randomized. 'Overall number of participants analyzed' indicates the number of participants with data available for outcome measure analysis at the specified timepoint.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo (DB)/Patisiran (OLE) | Change From Baseline at Month 12 in Kansas City Cardiomyopathy Questionnaire Overall Summary (KCCQ-OS) Score | -3.396 score on a scale | Standard Error 1.356 |
| Patisiran (DB+OLE) | Change From Baseline at Month 12 in Kansas City Cardiomyopathy Questionnaire Overall Summary (KCCQ-OS) Score | 0.478 score on a scale | Standard Error 1.363 |
p-value: 0.039795% CI: [0.176, 7.242]MMRM
Secondary
Composite Endpoint of All-cause Mortality and Frequency of All-cause Hospitalizations and Urgent HF Visits in All Participants
The hazard rate of all-cause mortality and all-cause hospitalizations and urgent HF visits was compared between treatment groups using a modified Andersen-Gill model. A hazard ratio \<1 represents a favorable outcome for patisiran.
Time frame: Up to Month 12
Population: All the participants from the Full Analysis Set \[all randomized participants who received any amount of study drug (either placebo or patisiran)\] were included in the data analysis for the outcome measure as pre-specified in the study protocol.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo (DB)/Patisiran (OLE) | Composite Endpoint of All-cause Mortality and Frequency of All-cause Hospitalizations and Urgent HF Visits in All Participants | 0.883 hazard ratio |
p-value: 0.560995% CI: [0.582, 1.341]Modified Andersen-Gill
Secondary
Composite Endpoint of All-Cause Mortality and Frequency of All-Cause Hospitalizations and Urgent HF Visits in Participants Not on Tafamidis at Baseline
The hazard rate of all-cause mortality and all-cause hospitalizations and urgent HF visits will be compared between treatment groups using an Andersen-Gill model. A hazard ratio \<1 represents a favorable outcome for patisiran.
Time frame: Up to Month 12
Population: Participants from the Full Analysis Set \[all randomized participants who received any amount of study drug (placebo or patisiran)\] and were not receiving tafamidis at Baseline were included in the data analysis for the outcome measure as pre-specified in the study protocol.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo (DB)/Patisiran (OLE) | Composite Endpoint of All-Cause Mortality and Frequency of All-Cause Hospitalizations and Urgent HF Visits in Participants Not on Tafamidis at Baseline | 0.997 hazard ratio |
p-value: 0.988895% CI: [0.62, 1.602]Andersen-Gill
Secondary
Composite Endpoint of All-Cause Mortality, Frequency of Cardiovascular (CV) Events (CV Hospitalizations and Urgent Heart Failure [HF] Visits) and Change From Baseline in 6-MWT Analyzed by Win Ratio
The composite endpoint was analyzed using the stratified win ratio method, stratified by baseline tafamidis use. This method combines all-cause mortality, frequency of CV events (CV hospitalizations and HF visits) and change from baseline in 6-MWT in a hierarchical fashion. This method makes within-stratum pairwise comparisons for all patisiran-placebo participant pairs in a sequential manner (first mortality, then CV events, then 6-MWT), with later steps evaluated only in the case of a tie on the prior step. Within each stratum, the win ratio is the total number of 'winners' divided by the total number of 'losers' in the active group. A win ratio \>1 represents a favorable outcome for patisiran.
Time frame: Up to Month 12
Population: Participants from the Full Analysis Set (all randomized participants who received any amount of study drug (either placebo or patisiran), grouped based on their use of tafamidis at Baseline as pre-specified in the study protocol.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo (DB)/Patisiran (OLE) | Composite Endpoint of All-Cause Mortality, Frequency of Cardiovascular (CV) Events (CV Hospitalizations and Urgent Heart Failure [HF] Visits) and Change From Baseline in 6-MWT Analyzed by Win Ratio | 1.22 win ratio |
| Patisiran (DB+OLE) | Composite Endpoint of All-Cause Mortality, Frequency of Cardiovascular (CV) Events (CV Hospitalizations and Urgent Heart Failure [HF] Visits) and Change From Baseline in 6-MWT Analyzed by Win Ratio | 1.28 win ratio |
p-value: 0.057495% CI: [0.99, 1.61]Z-test