Amyloid Neuropathies, Amyloid Neuropathies, Familial, Amyloidosis, Hereditary, Amyloidosis, Hereditary, Transthyretin-Related, Familial Transthyretin Cardiac Amyloidosis, Transthyretin (TTR) Mediated Familial Amyloidotic Cardiomyopathy (FAC)
Conditions
Keywords
Cardiomyopathy, Heart Failure, FAC, Amyloid, Transthyretin, TTR, RNAi therapeutic
Brief summary
The purpose of this study was to evaluate the safety and efficacy of revusiran (ALN-TTRSC) in patients with transthyretin (TTR) mediated Familial Amyloidotic Cardiomyopathy. Dosing has been discontinued; patients are being followed-up for safety.
Interventions
DRUGSterile Normal Saline (0.9% NaCl)
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 90 Years
Healthy volunteers
No
Inclusion criteria
* Documented TTR mutation * Amyloid deposits in cardiac or non-cardiac tissue * Medical history of heart failure * Evidence of cardiac involvement by echocardiogram
Exclusion criteria
* Has known primary amyloidosis (AL), leptomeningeal amyloidosis, non-FAC hereditary cardiomyopathy, hypertensive cardiomyopathy, or cardiomyopathy due to valvular heart disease * Has known peripheral vascular disease affecting ambulation * Has a Polyneuropathy Disability score \>2 * Has a New York Heart Association (NYHA) classification of IV
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 6 Minute Walk Distance (6-MWD) | 18 months | The difference between revusiran and placebo group in change from baseline to 18 months in the total distance walked in 6 minutes |
| Serum TTR Levels | 18 months | The difference between revusiran (ALN-TTRSC) and placebo group in the percent reduction in serum TTR levels over 18 months |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Kansas City Cardiomyopathy Questionnaire (KCCQ) | 18 months | The difference between revusiran (ALN-TTRSC) and placebo group in the change from Baseline to 18 months in the Kansas City Cardiomyopathy Questionnaire |
| Cardiovascular (CV) Mortality | 18 months | Number of cardiovascular-related deaths in the placebo group compared to the revusiran (ALN-TTRSC) treatment group |
| Composite Cardiovascular (CV) Mortality and Cardiovascular (CV) Hospitalization | 18 months | Number of cardiovascular-related deaths and cardiovascular-related hospitalizations in the placebo group compared to the revusiran (ALN-TTRSC) treatment group |
| All-cause Mortality | 18 months | Total number of deaths in the placebo group compared to the revusiran (ALN-TTRSC) treatment group |
| Cardiovascular (CV) Hospitalization | 18 months | Number of cardiovascular-related hospitalizations in the placebo group compared to the revusiran (ALN-TTRSC) treatment group |
| New York Heart Association (NYHA) Class | 18 months | The difference between revusiran (ALN-TTRSC) and placebo group in the change from baseline to 18 months in the NYHA class |
Countries
Belgium, Canada, France, Germany, Italy, Spain, Sweden, United Kingdom, United States
Participant flow
Recruitment details
A total of 206 patients with hereditary amyloid transthyretin (hATTR) cardiac amyloidosis were enrolled and randomized in the study.
Participants by arm
| Arm | Count |
|---|---|
| Revusiran All patients who received at least 1 dose of revusiran | 140 |
| Placebo All patients who received at least 1 dose of placebo | 66 |
| Total | 206 |
Baseline characteristics
| Characteristic | Placebo | Total | Revusiran |
|---|---|---|---|
| Age, Continuous | 66.2 years STANDARD_DEVIATION 9.52 | 67.8 years STANDARD_DEVIATION 9.4 | 68.6 years STANDARD_DEVIATION 9.28 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 5 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 65 Participants | 194 Participants | 129 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 7 Participants | 6 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 36 Participants | 104 Participants | 68 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 6 Participants | 6 Participants |
| Race (NIH/OMB) White | 29 Participants | 95 Participants | 66 Participants |
| Sex: Female, Male Female | 13 Participants | 48 Participants | 35 Participants |
| Sex: Female, Male Male | 53 Participants | 158 Participants | 105 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 23 / 140 | 7 / 66 |
| other Total, other adverse events | 136 / 140 | 62 / 66 |
| serious Total, serious adverse events | 83 / 140 | 34 / 66 |
Outcome results
Primary
6 Minute Walk Distance (6-MWD)
The difference between revusiran and placebo group in change from baseline to 18 months in the total distance walked in 6 minutes
Time frame: 18 months
Population: Study drug was discontinued early due to an imbalance in mortality observed between patients treated with revusiran and placebo. No patients had an 18-month visit, therefore, the endpoints cannot be calculated as data were not collected.
Primary
Serum TTR Levels
The difference between revusiran (ALN-TTRSC) and placebo group in the percent reduction in serum TTR levels over 18 months
Time frame: 18 months
Population: Study drug was discontinued early due to an imbalance in mortality observed between patients treated with revusiran and placebo. No patients had an 18-month visit, therefore, the endpoints cannot be calculated as data were not collected.
Secondary
All-cause Mortality
Total number of deaths in the placebo group compared to the revusiran (ALN-TTRSC) treatment group
Time frame: 18 months
Population: Study drug was discontinued early due to an imbalance in mortality observed between patients treated with revusiran and placebo. No patients had an 18-month visit, therefore, the endpoints cannot be calculated as data were not collected.
Secondary
Cardiovascular (CV) Hospitalization
Number of cardiovascular-related hospitalizations in the placebo group compared to the revusiran (ALN-TTRSC) treatment group
Time frame: 18 months
Population: Study drug was discontinued early due to an imbalance in mortality observed between patients treated with revusiran and placebo. No patients had an 18-month visit, therefore, the endpoints cannot be calculated as data were not collected.
Secondary
Cardiovascular (CV) Mortality
Number of cardiovascular-related deaths in the placebo group compared to the revusiran (ALN-TTRSC) treatment group
Time frame: 18 months
Population: Study drug was discontinued early due to an imbalance in mortality observed between patients treated with revusiran and placebo. No patients had an 18-month visit, therefore, the endpoints cannot be calculated as data were not collected.
Secondary
Composite Cardiovascular (CV) Mortality and Cardiovascular (CV) Hospitalization
Number of cardiovascular-related deaths and cardiovascular-related hospitalizations in the placebo group compared to the revusiran (ALN-TTRSC) treatment group
Time frame: 18 months
Population: Study drug was discontinued early due to an imbalance in mortality observed between patients treated with revusiran and placebo. No patients had an 18-month visit, therefore, the endpoints cannot be calculated as data were not collected.
Secondary
Kansas City Cardiomyopathy Questionnaire (KCCQ)
The difference between revusiran (ALN-TTRSC) and placebo group in the change from Baseline to 18 months in the Kansas City Cardiomyopathy Questionnaire
Time frame: 18 months
Population: Study drug was discontinued early due to an imbalance in mortality observed between patients treated with revusiran and placebo. No patients had an 18-month visit, therefore, the endpoints cannot be calculated as data were not collected.
Secondary
New York Heart Association (NYHA) Class
The difference between revusiran (ALN-TTRSC) and placebo group in the change from baseline to 18 months in the NYHA class
Time frame: 18 months
Population: Study drug was discontinued early due to an imbalance in mortality observed between patients treated with revusiran and placebo. No patients had an 18-month visit, therefore, the endpoints cannot be calculated as data were not collected.