Amyloid Cardiomyopathy, Amyloidosis, Cardiomyopathies, Heart Diseases, Transthyretin Amyloidosis
Conditions
Keywords
Amyloidosis, ATTR-CM, Transthyretin, Amyloid, TTR
Brief summary
Phase 3 efficacy and safety study to evaluate acoramidis (AG10) HCl 800 mg administered orally twice a day compared to placebo in subjects with symptomatic Transthyretin Amyloid Cardiomyopathy (ATTR-CM).
Detailed description
Transthyretin amyloid cardiomyopathy (ATTR-CM) is an underdiagnosed condition believed to affect more than 400,000 people worldwide. In ATTR-CM, the accumulation of transthyretin (TTR) amyloid results in thickening and stiffening of the heart, which often leads to heart failure or even death. There are two forms of ATTR-CM: * Wild Type\* This form of the condition primarily develops in older individuals who do not carry gene mutations. * Hereditary\* This form of the condition comes from gene mutations passed down in families. In this study we are researching the investigational drug acoramidis HCl 800 mg administered orally twice a day. Through the study, we want to evaluate the efficacy and safety of acoramidis in patients with ATTR-CM versus placebo. This is a 30 month, randomized, double-blind, placebo-controlled study. This means that, during the 30 month study, investigators conducting the research and study participants will not know whether the study participant is receiving acoramidis or placebo. The primary outcomes of the study are: 1. The impact of acoramidis versus placebo on the change in distance walked on the 6 minute walk test (6MWT) after 12 months of treatment compared to baseline. 2. The impact of acoramidis versus placebo on the hierarchical combination of All-Cause mortality, cumulative frequency of cardiovascular-related hospitalizations, change from baseline in NT-proBNP, and change in from baseline in 6MWT over a 30-month fixed treatment duration. At the end of 30 months, participants may be eligible to receive investigational acoramidis, and there is no placebo. This is called an open label extension. This separate study may help us better understand the safety related to taking acoramidis over a longer period of time.
Interventions
DRUGacoramidis
TTR stabilizer administered orally twice daily (BID)
DRUGPlacebo Oral Tablet
Non-active control administered orally twice daily (BID)
Sponsors
Eidos Therapeutics, a BridgeBio company
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 90 Years
Healthy volunteers
No
Inclusion criteria
* Have an established diagnosis of ATTR-CM with either wild-type TTR or variant TTR genotype * Have a history of heart failure evidenced by at least one prior hospitalization for heart failure or clinical evidence of heart failure without prior heart failure hospitalization manifested by signs or symptoms of volume overload or elevated intracardiac pressures or heart failure symptoms that required or require ongoing treatment with a diuretic. * New York Heart Association (NYHA) Class I-III symptoms due to ATTR cardiomyopathy. * On stable doses of cardiovascular medical therapy * Completed ≥150 m on the 6MWT on 2 tests that are within 15% of total distance walked prior to randomization * Biomarkers of myocardial wall stress, NT-proBNP level ≥300 pg/mL at screening * Have left ventricular wall (interventricular septum or left ventricular posterior wall) thickness ≥12 mm
Exclusion criteria
* Had acute myocardial infarction, acute coronary syndrome or coronary revascularization, or experienced stroke or transient ischemic attack within 90 days prior to screening * Has hemodynamic instability * Likely to undergo heart transplantation within a year of screening * Confirmed diagnosis of primary (light chain) amyloidosis * Biomarkers of myocardial wall stress, NT-proBNP level ≥8500 pg/mL at screening * Measure of kidney function, eGFR by MDRD formula \<15 mL/min/1.73 m2 * Current treatment with marketed drug products and other investigational agents for the treatment of ATTR-CM * Current treatment with calcium channel blockers with conduction system effects (e.g. verapamil, diltiazem). The use of dihydropyridine calcium channel blockers is allowed. The use of digitalis will only be allowed if required for management of atrial fibrillation with rapid ventricular response
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| A Hierarchical Combination of All-Cause Mortality, Cumulative Frequency of CV-related Hospitalization, Change From Baseline in NT-proBNP and Change From Baseline in 6MWT at the Last Available Visit Where Both Subjects Had Non-missing Assessments. | Baseline up to Month 30 | The endpoint was analyzed using Finkelstein-Schoenfeld method. The method combines all-cause mortality, cumulative frequency of CV-related hospitalizations, change from baseline in NT-proBNP and change from baseline in 6MWT in a hierarchical fashion. The method compares every participant with every other participant within strata, assigning a +1 to the better participant and a -1 to the worse participant and 0 if they are tied. Participants who had heart transplantation or implantation of a cardiac mechanical assist device were handled in the same manner as death. 'Win' represents a participant doing better based on hierarchical comparison. The reported unit is the total percent of wins for each treatment group from performing such a hierarchical comparison across stratification factors in the study. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to Month 30 in the Distance Walked During the 6 Minute Walk Test (6MWT) | Month 30 | 6MWT measures the total distance that a participant could walk in 6 minutes. Participants were asked to perform the test at a pace that was comfortable to them, with as many breaks as they needed. |
| Change From Baseline to Month 30 of the Kansas City Cardiomyopathy Questionnaire Overall Score (KCCQ-OS) | Month 30 | KCCQ is a 23-item participant-completed questionnaire that assesses health status and health-related quality of life in participants with heart failure. Eight domain scores were calculated for the KCCQ: Physical limitation, Social limitation, Quality of life, Self-efficacy, Symptom stability, Symptom frequency, Symptom burden, and Total symptoms (calculated as the mean of Symptom frequency and Symptom burden scores). The summary score of Overall Summary (calculated as mean of Physical limitation, Social limitation, Total symptoms, and Quality of life scores) was calculated. Domain and summary scores were scaled to range from 0 (minimum) to 100 (maximum); higher scores represent better health status. |
| Change From Baseline to Month 30 in Serum TTR (Prealbumin) Level | Month 30 | Serum TTR (Prealbumin) is an in vivo biomarker of stabilization. |
| All-cause Mortality by Month 30, Including Death Due to Any Cause, Heart Transplant or Cardiac Mechanical Assist Device (CMAD) | Baseline up to Month 30 | Number of deaths due to any cause was analyzed. Participants who had heart transplantation or implantation of a CMAD were handled in the same manner as death. |
Countries
Australia, Belgium, Brazil, Canada, Czechia, Denmark, Greece, Ireland, Israel, Italy, Netherlands, New Zealand, Poland, Portugal, South Korea, Spain, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Acoramidis HCl 800 mg Participants with symptomatic ATTR-CM received 800 mg acoramidis HCl BID (two 400 mg acoramidis HCl tablets, each equivalent to 356 mg acoramidis \[active moiety\]) | 421 |
| Placebo Participants with symptomatic ATTR-CM received matching placebo (two matching placebo tablets BID) | 211 |
| Total | 632 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 75 | 51 |
| Overall Study | Withdrawal of Consent | 15 | 6 |
Baseline characteristics
| Characteristic | Placebo | Acoramidis HCl 800 mg | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 202 Participants | 409 Participants | 611 Participants |
| Age, Categorical Between 18 and 65 years | 9 Participants | 12 Participants | 21 Participants |
| Age, Continuous | 77.09 years STANDARD_DEVIATION 6.763 | 77.37 years STANDARD_DEVIATION 6.45 | 77.27 years STANDARD_DEVIATION 6.552 |
| Distance Walked During the 6 Minute Walk Test (6MWT) | 348.37 Meter STANDARD_DEVIATION 93.564 | 361.21 Meter STANDARD_DEVIATION 103.705 | 356.91 Meter STANDARD_DEVIATION 100.531 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 4 Participants | 8 Participants | 12 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 199 Participants | 401 Participants | 600 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 8 Participants | 12 Participants | 20 Participants |
| Kansas City Cardiomyopathy Questionnaire Overall Score (KCCQ-OS) | 70.31 units on a scale STANDARD_DEVIATION 20.541 | 71.52 units on a scale STANDARD_DEVIATION 19.387 | 71.12 units on a scale STANDARD_DEVIATION 19.773 |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 3 Participants | 10 Participants | 13 Participants |
| Race (NIH/OMB) Black or African American | 10 Participants | 20 Participants | 30 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 9 Participants | 21 Participants | 30 Participants |
| Race (NIH/OMB) White | 187 Participants | 368 Participants | 555 Participants |
| Serum TTR (Prealbumin) Level | 23.63 mg/dL STANDARD_DEVIATION 6.07 | 23.16 mg/dL STANDARD_DEVIATION 5.643 | 23.32 mg/dL STANDARD_DEVIATION 5.788 |
| Sex: Female, Male Female | 25 Participants | 37 Participants | 62 Participants |
| Sex: Female, Male Male | 186 Participants | 384 Participants | 570 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 84 / 421 | 55 / 211 |
| other Total, other adverse events | 410 / 421 | 199 / 211 |
| serious Total, serious adverse events | 230 / 421 | 137 / 211 |
Outcome results
Primary
A Hierarchical Combination of All-Cause Mortality, Cumulative Frequency of CV-related Hospitalization, Change From Baseline in NT-proBNP and Change From Baseline in 6MWT at the Last Available Visit Where Both Subjects Had Non-missing Assessments.
The endpoint was analyzed using Finkelstein-Schoenfeld method. The method combines all-cause mortality, cumulative frequency of CV-related hospitalizations, change from baseline in NT-proBNP and change from baseline in 6MWT in a hierarchical fashion. The method compares every participant with every other participant within strata, assigning a +1 to the better participant and a -1 to the worse participant and 0 if they are tied. Participants who had heart transplantation or implantation of a cardiac mechanical assist device were handled in the same manner as death. 'Win' represents a participant doing better based on hierarchical comparison. The reported unit is the total percent of wins for each treatment group from performing such a hierarchical comparison across stratification factors in the study.
Time frame: Baseline up to Month 30
Population: The mITT population includes subjects who meet the definition of ITT which includes all randomized subjects who received at least one dose of IMP and have at least one post baseline efficacy assessment as well as an additional requirement which is to have a baseline eGFR \>= 30 mL/min/1.73 m\^2 . Subjects in this population were analyzed according to their assigned randomized treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Acoramidis HCl 800 mg | A Hierarchical Combination of All-Cause Mortality, Cumulative Frequency of CV-related Hospitalization, Change From Baseline in NT-proBNP and Change From Baseline in 6MWT at the Last Available Visit Where Both Subjects Had Non-missing Assessments. | 63.7 Percent of Wins from Win Ratio |
| Placebo | A Hierarchical Combination of All-Cause Mortality, Cumulative Frequency of CV-related Hospitalization, Change From Baseline in NT-proBNP and Change From Baseline in 6MWT at the Last Available Visit Where Both Subjects Had Non-missing Assessments. | 35.9 Percent of Wins from Win Ratio |
p-value: <0.0001Finkelstein-Schoenfeld Method
Secondary
All-cause Mortality by Month 30, Including Death Due to Any Cause, Heart Transplant or Cardiac Mechanical Assist Device (CMAD)
Number of deaths due to any cause was analyzed. Participants who had heart transplantation or implantation of a CMAD were handled in the same manner as death.
Time frame: Baseline up to Month 30
Population: The mITT population includes subjects who meet the definition of ITT which includes all randomized subjects who received at least one dose of IMP and have at least one post baseline efficacy assessment as well as an additional requirement which is to have a baseline eGFR \>= 30 mL/min/1.73 m\^2 . Subjects in this population were analyzed according to their assigned randomized treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Acoramidis HCl 800 mg | All-cause Mortality by Month 30, Including Death Due to Any Cause, Heart Transplant or Cardiac Mechanical Assist Device (CMAD) | 79 Participants |
| Placebo | All-cause Mortality by Month 30, Including Death Due to Any Cause, Heart Transplant or Cardiac Mechanical Assist Device (CMAD) | 52 Participants |
p-value: 0.0569Cochran-Mantel-Haenszel
Secondary
Change From Baseline to Month 30 in Serum TTR (Prealbumin) Level
Serum TTR (Prealbumin) is an in vivo biomarker of stabilization.
Time frame: Month 30
Population: The mITT population includes subjects who meet the definition of ITT which includes all randomized subjects who received at least one dose of IMP and have at least one post baseline efficacy assessment as well as an additional requirement which is to have a baseline eGFR \>= 30 mL/min/1.73 m\^2 . Subjects in this population were analyzed according to their assigned randomized treatment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Acoramidis HCl 800 mg | Change From Baseline to Month 30 in Serum TTR (Prealbumin) Level | 5.78 mg/dL | Standard Error 0.391 |
| Placebo | Change From Baseline to Month 30 in Serum TTR (Prealbumin) Level | -1.32 mg/dL | Standard Error 0.541 |
Comparison: LS means are from a MMRM model with treatment group, visit, randomization stratification factors of genotype, NT-proBNP level and eGFR level (as recorded in IXRS) and treatment group-by-visit interaction as factors, and baseline value as covariate. Missing measurements due to early discontinuation of study treatment and due to death were imputed using the Jump to Reference (J2R) method and sampling with replacement from the worst 5% of observed values, respectively, as specified in study SAP.p-value: <0.000196% CI: [5.73, 8.46]Mixed Models Analysis
Secondary
Change From Baseline to Month 30 in the Distance Walked During the 6 Minute Walk Test (6MWT)
6MWT measures the total distance that a participant could walk in 6 minutes. Participants were asked to perform the test at a pace that was comfortable to them, with as many breaks as they needed.
Time frame: Month 30
Population: The mITT population includes subjects who meet the definition of ITT which includes all randomized subjects who received at least one dose of IMP and have at least one post baseline efficacy assessment as well as an additional requirement which is to have a baseline eGFR \>= 30 mL/min/1.73 m\^2 . Subjects in this population were analyzed according to their assigned randomized treatment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Acoramidis HCl 800 mg | Change From Baseline to Month 30 in the Distance Walked During the 6 Minute Walk Test (6MWT) | -64.65 Meter | Standard Error 5.508 |
| Placebo | Change From Baseline to Month 30 in the Distance Walked During the 6 Minute Walk Test (6MWT) | -104.29 Meter | Standard Error 7.772 |
Comparison: LS means are from a MMRM model with treatment group, visit, randomization stratification factors of genotype, NT-proBNP level and eGFR level (as recorded in IXRS) and treatment group-by-visit interaction as factors, and baseline value as covariate. Missing measurements due to early discontinuation of study treatment and due to death were imputed using the Jump to Reference (J2R) method and sampling with replacement from the worst 5% of observed values, respectively, as specified in study SAP.p-value: <0.000196% CI: [20.18, 59.1]Mixed Models Analysis
Secondary
Change From Baseline to Month 30 of the Kansas City Cardiomyopathy Questionnaire Overall Score (KCCQ-OS)
KCCQ is a 23-item participant-completed questionnaire that assesses health status and health-related quality of life in participants with heart failure. Eight domain scores were calculated for the KCCQ: Physical limitation, Social limitation, Quality of life, Self-efficacy, Symptom stability, Symptom frequency, Symptom burden, and Total symptoms (calculated as the mean of Symptom frequency and Symptom burden scores). The summary score of Overall Summary (calculated as mean of Physical limitation, Social limitation, Total symptoms, and Quality of life scores) was calculated. Domain and summary scores were scaled to range from 0 (minimum) to 100 (maximum); higher scores represent better health status.
Time frame: Month 30
Population: The mITT population includes subjects who meet the definition of ITT which includes all randomized subjects who received at least one dose of IMP and have at least one post baseline efficacy assessment as well as an additional requirement which is to have a baseline eGFR \>= 30 mL/min/1.73 m\^2 . Subjects in this population were analyzed according to their assigned randomized treatment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Acoramidis HCl 800 mg | Change From Baseline to Month 30 of the Kansas City Cardiomyopathy Questionnaire Overall Score (KCCQ-OS) | -11.48 Score on a scale | Standard Error 1.181 |
| Placebo | Change From Baseline to Month 30 of the Kansas City Cardiomyopathy Questionnaire Overall Score (KCCQ-OS) | -21.42 Score on a scale | Standard Error 1.651 |
Comparison: LS means are from a MMRM model with treatment group, visit, randomization stratification factors of genotype, NT-proBNP level and eGFR level (as recorded in IXRS) and treatment group-by-visit interaction as factors, and baseline value as covariate. Missing measurements due to early discontinuation of study treatment and due to death were imputed using the Jump to Reference (J2R) method and sampling with replacement from the worst 5% of observed values, respectively, as specified in study SAP.p-value: <0.000196% CI: [5.79, 14.1]Mixed Models Analysis