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).
Brief Title
Efficacy and Safety of AG10 in Subjects With Transthyretin Amyloid Cardiomyopathy
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.
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.
Categories
Completion Date
Completion Date Type
Actual
Conditions
Amyloidosis
Amyloid Cardiomyopathy
Transthyretin Amyloidosis
Cardiomyopathies
Heart Diseases
Eligibility Criteria
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
* 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
Inclusion Criteria
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
* 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
Gender
All
Gender Based
false
Keywords
Amyloidosis
ATTR-CM
Transthyretin
Amyloid
TTR
Healthy Volunteers
No
Last Update Post Date
Last Update Post Date Type
Actual
Last Update Submit Date
Maximum Age
90 Years
Minimum Age
18 Years
NCT Id
NCT03860935
Org Class
Industry
Org Full Name
Eidos Therapeutics, a BridgeBio company
Org Study Id
AG10-301
Overall Status
Completed
Phases
Phase 3
Primary Completion Date
Primary Completion Date Type
Actual
Official Title
A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study of the Efficacy and Safety of AG10 in Subjects With Symptomatic Transthyretin Amyloid Cardiomyopathy (ATTRibute-CM Trial)
Primary Outcomes
Outcome Description
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.
Outcome Measure
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.
Outcome Time Frame
Baseline up to Month 30
Secondary Ids
Secondary Id
2018-004280-32
Secondary Outcomes
Outcome Description
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.
Outcome Time Frame
Month 30
Outcome Measure
Change From Baseline to Month 30 in the Distance Walked During the 6 Minute Walk Test (6MWT)
Outcome Description
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.
Outcome Time Frame
Month 30
Outcome Measure
Change From Baseline to Month 30 of the Kansas City Cardiomyopathy Questionnaire Overall Score (KCCQ-OS)
Outcome Description
Serum TTR (Prealbumin) is an in vivo biomarker of stabilization.
Outcome Time Frame
Month 30
Outcome Measure
Change From Baseline to Month 30 in Serum TTR (Prealbumin) Level
Outcome Description
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.
Outcome Time Frame
Baseline up to Month 30
Outcome Measure
All-cause Mortality by Month 30, Including Death Due to Any Cause, Heart Transplant or Cardiac Mechanical Assist Device (CMAD)
Start Date
Start Date Type
Actual
Status Verified Date
First Post Date
First Post Date Type
Actual
First Submit Date
First Submit QC Date
Std Ages
Adult
Older Adult
Maximum Age Number (converted to Years and rounded down)
90
Minimum Age Number (converted to Years and rounded down)
18
Investigators
Investigator Type
Principal Investigator
Investigator Name
James Tauras
Investigator Email
jtauras@montefiore.org