This study will evaluate the efficacy and safety of vutrisiran 25 mg administered subcutaneously (SC) once every 3 months (q3M) compared to placebo in participants with ATTR amyloidosis with cardiomyopathy.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
655
Vutrisiran will be administered by SC injection.
Sterile normal saline (0.9% NaCl) will be administered by SC injection.
Composite Endpoint of All-Cause Mortality and Recurrent Cardiovascular (CV) Events (CV Hospitalizations and Urgent Heart Failure [HF] Visits) in the Overall Population
All-cause mortality and recurrent CV events (CV hospitalizations and urgent HF visits) were compared between treatment groups using a modified Andersen-Gill model with a robust variance. All-cause mortality included heart transplantation and LVAD placement events along with deaths; recurrent CV events included CV hospitalizations and urgent HF visits. The number of participants with at least one CV event or all-cause mortality event have been reported here. No imputation was done for participants who dropped out early for the primary analysis of this composite outcome endpoint.
Time frame: Up to Month 36
Composite Endpoint of All-Cause Mortality and Recurrent CV Events (CV Hospitalizations and Urgent HF Visits) in the Vutrisiran Monotherapy Subgroup
All-cause mortality and recurrent CV events (CV hospitalizations and urgent HF visits) were compared between treatment groups using a modified Andersen-Gill model with a robust variance. All-cause mortality included heart transplantation and LVAD placement events along with deaths; recurrent CV events included CV hospitalizations and urgent HF visits. The number of participants with at least one CV event or all-cause mortality event have been reported here. No imputation was done for participants who dropped out early for the primary analysis of this composite outcome endpoint.
Time frame: Up to Month 36
Change From Baseline in 6-Minute Walk Test (6-MWT) in the Overall Population
The 6-MWT is an assessment of functional exercise capacity. Participants are instructed to walk back and forth along a flat, straight path, typically 30 meters in length, for a duration of 6 minutes. The total distance covered in meters is recorded at the end of 6 minutes. A longer distance reflects a better outcome. Analysis was based on the mixed-effect model of repeated measures (MMRM). Missing change values due to amyloidosis disease progression and death were imputed using sampling with replacement from the worst 10% of observed values, as specified in the statistical analysis plan (SAP).
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Clinical Trial Site
La Mesa, California, United States
Clinical Trial Site
Los Angeles, California, United States
Clinical Trial Site
Stanford, California, United States
Clinical Trial Site
Washington D.C., District of Columbia, United States
Clinical Trial Site
Gainesville, Georgia, United States
Clinical Trial Site
Chicago, Illinois, United States
Clinical Trial Site
Evanston, Illinois, United States
Clinical Trial Site
Boston, Massachusetts, United States
Clinical Trial Site
Boston, Massachusetts, United States
Clinical Trial Site
Rochester, Minnesota, United States
...and 109 more locations
Time frame: Baseline to Month 30
Change From Baseline in 6-MWT in the Vutrisiran Monotherapy Subgroup
The 6-MWT is an assessment of functional exercise capacity. Participants are instructed to walk back and forth along a flat, straight path, typically 30 meters in length, for a duration of 6 minutes. The total distance covered in meters is recorded at the end of 6 minutes. A longer distance reflects a better outcome. Analysis was based on the MMRM. Missing change values due to amyloidosis disease progression and death were imputed using sampling with replacement from the worst 10% of observed values, as specified in the SAP.
Time frame: Baseline to Month 30
Change From Baseline in the Kansas City Cardiomyopathy Questionnaire Overall Summary (KCCQ-OS) Score in the Overall Population
The KCCQ is a 23-item self-administered questionnaire quantifying 6 domains (symptoms \[frequency and burden\], physical function, quality of life (QoL), social limitation, self-efficacy, and symptom stability) and 2 summary scores (clinical and overall summary \[OS\]). Scores were generated for each domain and transformed to a range of 0-100, in which higher scores reflect better health status. KCCQ- overall summary score was average of domains- physical function, total symptoms (average of symptom frequency and burden), QoL, and social limitation, and transformed to a single score which ranged from 0 (worst) - 100 (the best possible status), where the higher score reflected better health status. Analysis was based on the MMRM.
Time frame: Baseline to Month 30
Change From Baseline in the KCCQ-OS Score in the Vutrisiran Monotherapy Subgroup
The KCCQ is a 23-item self-administered questionnaire quantifying 6 domains (symptoms \[frequency and burden\], physical function, QoL, social limitation, self-efficacy, and symptom stability) and 2 summary scores (clinical and OS). Scores were generated for each domain and transformed to a range of 0-100, in which higher scores reflect better health status. KCCQ- overall summary score was average of domains- physical function, total symptoms (average of symptom frequency and burden), QoL, and social limitation, and transformed to a single score which ranged from 0 (worst) - 100 (the best possible status), where the higher score reflected better health status. Analysis was based on the MMRM.
Time frame: Baseline to Month 30
All-cause Mortality in the Overall Population and Vutrisiran Monotherapy Subgroup
All-cause mortality also included heart transplantation and LVAD placement events along with deaths; recurrent CV events included CV hospitalizations and urgent HF visits.
Time frame: Up to 42 months
Percentage of Participants With Change in NYHA Class at Month 30 in the Overall Population
NYHA class is a clinical assessment of symptoms resulting from heart failure. In NYHA functional classification system places participants in 1 of 4 categories based on limitations of physical activity. Class I denotes no symptoms and no limitation of physical activity; II, slight limitation, resulting in symptoms with ordinary physical activity; III, marked limitation, resulting in symptoms with less than ordinary physical activity; and IV, symptoms at rest. Here, the participants with a change in NYHA class have been reported in two categories: 1\) participants who had no change or had improvement in the NYHA class (lower class) from baseline and 2) participants who had a worsened NYHA class from baseline (higher class). Values have been rounded off to a single decimal.
Time frame: Baseline to Month 30
Percentage of Participants With Change in NYHA Class at Month 30 in the Vutrisiran Monotherapy Subgroup
NYHA class is a clinical assessment of symptoms resulting from heart failure. In NYHA functional classification system places participants in 1 of 4 categories based on limitations of physical activity. Class I denotes no symptoms and no limitation of physical activity; II, slight limitation, resulting in symptoms with ordinary physical activity; III, marked limitation, resulting in symptoms with less than ordinary physical activity; and IV, symptoms at rest. Here, the participants with a change in NYHA class have been reported in two categories: 1\) participants who had no change or had improvement in the NYHA class (lower class) from baseline and 2) participants who had a worsened NYHA class from baseline (higher class). Values have been rounded off to a single decimal.
Time frame: Baseline to Month 30