Efficacy and Safety of AG10 in Subjects With Transthyretin Amyloid Cardiomyopathy

Phase 3

Completed

Conditions: Transthyretin Amyloidosis
Amyloidosis
Amyloid Cardiomyopathy
Cardiomyopathies
Heart Diseases

Interventions: Drug: Placebo Oral Tablet
Drug: acoramidis

Registration Number: NCT03860935

Lead Sponsor: Eidos Therapeutics, a BridgeBio company

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 632

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo	Placebo Oral Tablet	Subjects will receive placebo to match twice daily. 6MWT primary outcome will be assessed at the end of 12 months. The hierarchical combination of All-Cause mortality, cumulative frequency of cardiovascular-related hospitalizations, change from baseline in NT-proBNP levels, and change from baseline in distance walked on the 6MWT will be assessed after 30 months of treatment.
acoramidis HCl 800 mg	acoramidis	Subjects will receive acoramidis HCl 800 mg twice daily. 6MWT primary outcome will be assessed at the end of 12 months. The hierarchical combination of All-Cause mortality, cumulative frequency of cardiovascular-related hospitalizations, change from baseline in NT-proBNP levels, and change from baseline in distance walked on the 6MWT will be assessed after 30 months of treatment.

Primary Outcome Measures

Name	Time	Method
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 Outcome Measures

Name	Time	Method
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.

Trial Locations

Locations (103): Cedars-Sinai Medical Center
🇺🇸
Los Angeles, California, United States
Pacific Heart Institute
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Santa Monica, California, United States
University of Colorado Hospital - Anschutz Medical Campus
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Aurora, Colorado, United States
Yale School of Medicine
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New Haven, Connecticut, United States
MedStar Washington Hospital Center
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Washington, District of Columbia, United States
University of Miami - Sylvester Comprehensive Cancer Center
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Miami, Florida, United States
Piedmont Heart Institute Athens
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Athens, Georgia, United States
Emory Heart and Vascular Center
🇺🇸
Atlanta, Georgia, United States
Northwestern University
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Chicago, Illinois, United States
The University of Chicago Medical Center
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Chicago, Illinois, United States
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Cedars-Sinai Medical Center
🇺🇸Los Angeles, California, United States