Efficacy and Safety of AG10 in Subjects With Transthyretin Amyloid Cardiomyopathy
- Conditions
- Transthyretin AmyloidosisAmyloidosisAmyloid CardiomyopathyCardiomyopathiesHeart Diseases
- Interventions
- Drug: Placebo Oral Tablet
- 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
- 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
- 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)
Piedmont Heart Institute Athens
🇺🇸Athens, Georgia, United States
Northwestern University
🇺🇸Chicago, Illinois, United States
The University of Chicago Medical Center
🇺🇸Chicago, Illinois, United States
NorthShore University Health System
🇺🇸Evanston, Illinois, United States
MedStar Medical Group Cardiology at Franklin Square Medical Center
🇺🇸Baltimore, Maryland, United States
Saint Elizabeth's Medical Center
🇺🇸Boston, Massachusetts, United States
North Shore University Hospital
🇺🇸Manhasset, New York, United States
Cleveland Clinic
🇺🇸Cleveland, Ohio, United States
Hospital Cárdio Pulmonar
🇧🇷Salvador, Bahia, Brazil
Royal Free Hospital
🇬🇧London, England, United Kingdom
Box Hill Hospital
🇦🇺Box Hill, Australia
Royal Adelaide Hospital
🇦🇺Adelaide, Australia
Royal Hobart Hospital
🇦🇺Hobart, Australia
Universita degli Studi di Roma La Sapienza - Umberto I Policlinico di Roma
🇮🇹Roma, Italy
Waikato Hospital
🇳🇿Hamilton, Waikato, New Zealand
Indiana University
🇺🇸Indianapolis, Indiana, United States
University of Miami - Sylvester Comprehensive Cancer Center
🇺🇸Miami, Florida, United States
University of Washington School of Medicine
🇺🇸Seattle, Washington, United States
Cedars-Sinai Medical Center
🇺🇸Los Angeles, California, United States
Pacific Heart Institute
🇺🇸Santa Monica, California, United States
Emory Heart and Vascular Center
🇺🇸Atlanta, Georgia, United States
Washington University School of Medicine
🇺🇸Saint Louis, Missouri, United States
New York University Langone Health
🇺🇸New York, New York, United States
Columbia University Medical Center
🇺🇸New York, New York, United States
Mount Sinai Hospital
🇺🇸New York, New York, United States
Laurelton Heart Specialist
🇺🇸Rosedale, New York, United States
Penn Presbyterian Medical Center
🇺🇸Philadelphia, Pennsylvania, United States
Allegheny General Hospital
🇺🇸Pittsburgh, Pennsylvania, United States
University of Pittsburgh
🇺🇸Pittsburgh, Pennsylvania, United States
University of Texas Southwestern Medical Center
🇺🇸Dallas, Texas, United States
Carilion Clinic Roanoke Heart Institute
🇺🇸Roanoke, Virginia, United States
Providence Sacred Heart Medical Center
🇺🇸Spokane, Washington, United States
Duke University Health System
🇺🇸Durham, North Carolina, United States
University of Utah
🇺🇸Salt Lake City, Utah, United States
Santa Casa de Misericordia - Porto Alegre
🇧🇷Porto Alegre, Rio Grande Do Sul, Brazil
MedStar Washington Hospital Center
🇺🇸Washington, District of Columbia, United States
Toronto Heart Centre
🇨🇦Toronto, Ontario, Canada
Universitair Ziekenhuis Leuven
🇧🇪Leuven, Belgium
INCOR
🇧🇷São Paulo, Sao Paulo, Brazil
Centro Hospitalar de Lisboa Norte EPE- Hospital Santa Maria
🇵🇹Lisboa, Portugal
Centro Hospitalar do Porto
🇵🇹Porto, Portugal
Newark Beth Israel Medical Center
🇺🇸Newark, New Jersey, United States
University of Calgary
🇨🇦Calgary, Alberta, Canada
CAPED - Centro Avançado de Pesquisa e Estudos para o Diagnóstico
🇧🇷Ribeirão Preto, Sao Paulo, Brazil
Azienda Ospedaliero Universitaria di Bologna Policlinico Sant'Orsola-Malpighi
🇮🇹Bologna, Italy
Universitair Medisch Centrum Utrecht
🇳🇱Utrecht, Netherlands
Montreal Heart Institute
🇨🇦Montréal, Canada
Ospedale San Donato
🇮🇹Arezzo, Italy
University of British Columbia
🇨🇦Vancouver, British Columbia, Canada
Universitair Medisch Centrum Groningen
🇳🇱Groningen, Netherlands
National Institute of Cardiology
🇵🇱Warsaw, Poland
Prisma Health - Greenville Memorial Hospital
🇺🇸Greenville, South Carolina, United States
Boston University School of Medicine
🇺🇸Boston, Massachusetts, United States
Instituto de Cardiologia do Rio Grande do Sul
🇧🇷Porto Alegre, Brazil
Centre Hospitalier de L'Universite de Montreal - Hôpital Notre-Dame
🇨🇦Montréal, Quebec, Canada
Hadassah University Hospital Ein Kerem
🇮🇱Jerusalem, Israel
Maastricht Universitair Medisch Centrum
🇳🇱Maastricht, Limburg, Netherlands
Seoul National University Hospital
🇰🇷Seoul, Gyeonggi-Do, Korea, Republic of
Mayo Clinic
🇺🇸Rochester, Minnesota, United States
Oregon Health and Science University
🇺🇸Portland, Oregon, United States
Fiona Stanley Hospital
🇦🇺Murdoch, Australia
Saint Vincent's Hospital Sydney
🇦🇺Sydney, Australia
Princess Alexandra Hospital
🇦🇺Woolloongabba, Australia
Ziekenhuis Oost-Limburg - Campus Sint-Jan
🇧🇪Genk, Limburg, Belgium
Jessa Ziekenhuis - Campus Virga Jesse
🇧🇪Hasselt, Limburg, Belgium
Algemeen Ziekenhuis Sint-Jan Brugge-Oostende
🇧🇪Brugge, West Vlaanderen, Belgium
Onze-Lieve-Vrouw Ziekenhuis Aalst
🇧🇪Aalst, Belgium
CancerCare Manitoba - St. Boniface
🇨🇦Winnipeg, Manitoba, Canada
University of Toronto
🇨🇦Toronto, Ontario, Canada
Halifax Infirmary
🇨🇦Halifax, Nova Scotia, Canada
Hôpital du Sacré-Coeur de Montréal
🇨🇦Montréal, Quebec, Canada
General University Hospital in Prague
🇨🇿Nové Město, Czechia
Institut Universitaire de Cardiologie et de Pneumologie de Québec
🇨🇦Quebec City, Quebec, Canada
Hôpital régional de Rimouski
🇨🇦Rimouski, Quebec, Canada
St. Anne´s University Hospital
🇨🇿Brno Střed, Czechia
Institute for Clinical and Experimental Medicine
🇨🇿Prague, Czechia
Aarhus Universitetshospital
🇩🇰Aarhus, Dinamarca, Denmark
Mater Misericordiae University Hospital
🇮🇪Dublin, Ireland
Alexandra General Hospital of Athens
🇬🇷Athens, Attica, Greece
Saint Vincents University Hospital
🇮🇪Dublin, Ireland
The Chaim Sheba Medical Center
🇮🇱Tel Hashomer, Israel
Fondazione IRCCS Policlinico San Matteo
🇮🇹Pavia, Italy
Azienda Ospedaliero - Universitaria Careggi
🇮🇹Firenze, Italy
Seoul National University Bundang Hospital
🇰🇷Seongnam-si, Gyeonggi-Do, Korea, Republic of
Fondazione Toscana Gabriele Monasterio per la Ricerca Medica e di Sanità Pubblica
🇮🇹Pisa, Italy
Middlemore Hospital
🇳🇿Otahuhu, Auckland, New Zealand
Ospedale degli Infermi
🇮🇹Rimini, Italy
Clínica Universidad de Navarra
🇪🇸Pamplona, Navarra, Spain
Clinica Universidad de Navarra Madrid
🇪🇸Madrid, Spain
Hospital Universitari Germans Trias i Pujol
🇪🇸Barcelona, Spain
Hospital Juan Ramón Jiménez
🇪🇸Huelva, Spain
Hospital Universitario Puerta de Hierro
🇪🇸Madrid, Spain
Hospital Son Llàtzer
🇪🇸Palma De Mallorca, Spain
Hospital Clínico Universitario de Santiago de Compostela
🇪🇸Santiago De Compostela, Spain
Richmond Pharmacology
🇬🇧London, United Kingdom
Hospital Clínico Universitario de Valencia
🇪🇸Valencia, Spain
University of Colorado Hospital - Anschutz Medical Campus
🇺🇸Aurora, Colorado, United States
University of North Carolina - Chapel Hill
🇺🇸Chapel Hill, North Carolina, United States
Virginia Commonwealth University Medical Center
🇺🇸Richmond, Virginia, United States
Yale School of Medicine
🇺🇸New Haven, Connecticut, United States
The Medical University of South Carolina
🇺🇸Charleston, South Carolina, United States
Saint Luke's Hospital - Kansas City
🇺🇸Kansas City, Missouri, United States
Montefiore Medical Center
🇺🇸Bronx, New York, United States