Heart Diseases Clinical Trial
— ATTRibute-CMOfficial 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)
Verified date | July 2023 |
Source | Eidos Therapeutics, a BridgeBio company |
Contact | n/a |
Is FDA regulated | No |
Health authority | |
Study type | Interventional |
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).
Status | Completed |
Enrollment | 632 |
Est. completion date | May 11, 2023 |
Est. primary completion date | May 11, 2023 |
Accepts healthy volunteers | No |
Gender | All |
Age group | 18 Years to 90 Years |
Eligibility | 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 |
Country | Name | City | State |
---|---|---|---|
Australia | Royal Adelaide Hospital | Adelaide | |
Australia | Box Hill Hospital | Box Hill | |
Australia | Royal Hobart Hospital | Hobart | |
Australia | Fiona Stanley Hospital | Murdoch | |
Australia | Saint Vincent's Hospital Sydney | Sydney | |
Australia | Princess Alexandra Hospital | Woolloongabba | |
Belgium | Onze-Lieve-Vrouw Ziekenhuis Aalst | Aalst | |
Belgium | Algemeen Ziekenhuis Sint-Jan Brugge-Oostende | Brugge | West Vlaanderen |
Belgium | Ziekenhuis Oost-Limburg - Campus Sint-Jan | Genk | Limburg |
Belgium | Jessa Ziekenhuis - Campus Virga Jesse | Hasselt | Limburg |
Belgium | Universitair Ziekenhuis Leuven | Leuven | |
Brazil | Instituto de Cardiologia do Rio Grande do Sul | Porto Alegre | |
Brazil | Santa Casa de Misericordia - Porto Alegre | Porto Alegre | Rio Grande Do Sul |
Brazil | CAPED - Centro Avançado de Pesquisa e Estudos para o Diagnóstico | Ribeirão Preto | Sao Paulo |
Brazil | Hospital Cárdio Pulmonar | Salvador | Bahia |
Brazil | INCOR | São Paulo | Sao Paulo |
Canada | University of Calgary | Calgary | Alberta |
Canada | Halifax Infirmary | Halifax | Nova Scotia |
Canada | Centre Hospitalier de L'Universite de Montreal - Hôpital Notre-Dame | Montréal | Quebec |
Canada | Hôpital du Sacré-Coeur de Montréal | Montréal | Quebec |
Canada | Montreal Heart Institute | Montréal | |
Canada | Institut Universitaire de Cardiologie et de Pneumologie de Québec | Quebec City | Quebec |
Canada | Hôpital régional de Rimouski | Rimouski | Quebec |
Canada | Toronto Heart Centre | Toronto | Ontario |
Canada | University of Toronto | Toronto | Ontario |
Canada | University of British Columbia | Vancouver | British Columbia |
Canada | CancerCare Manitoba - St. Boniface | Winnipeg | Manitoba |
Czechia | St. Anne´s University Hospital | Brno Stred | |
Czechia | General University Hospital in Prague | Nové Mesto | |
Czechia | Institute for Clinical and Experimental Medicine | Prague | |
Denmark | Aarhus Universitetshospital | Aarhus | Dinamarca |
Greece | Alexandra General Hospital of Athens | Athens | Attica |
Ireland | Mater Misericordiae University Hospital | Dublin | |
Ireland | Saint Vincents University Hospital | Dublin | |
Israel | Hadassah University Hospital Ein Kerem | Jerusalem | |
Israel | The Chaim Sheba Medical Center | Tel Hashomer | |
Italy | Ospedale San Donato | Arezzo | |
Italy | Azienda Ospedaliero Universitaria di Bologna Policlinico Sant'Orsola-Malpighi | Bologna | |
Italy | Azienda Ospedaliero - Universitaria Careggi | Firenze | |
Italy | Fondazione IRCCS Policlinico San Matteo | Pavia | |
Italy | Fondazione Toscana Gabriele Monasterio per la Ricerca Medica e di Sanità Pubblica | Pisa | |
Italy | Ospedale degli Infermi | Rimini | |
Italy | Universita degli Studi di Roma La Sapienza - Umberto I Policlinico di Roma | Roma | |
Korea, Republic of | Seoul National University Bundang Hospital | Seongnam-si | Gyeonggi-Do |
Korea, Republic of | Seoul National University Hospital | Seoul | Gyeonggi-Do |
Netherlands | Universitair Medisch Centrum Groningen | Groningen | |
Netherlands | Maastricht Universitair Medisch Centrum | Maastricht | Limburg |
Netherlands | Universitair Medisch Centrum Utrecht | Utrecht | |
New Zealand | Waikato Hospital | Hamilton | Waikato |
New Zealand | Middlemore Hospital | Otahuhu | Auckland |
Poland | National Institute of Cardiology | Warsaw | |
Portugal | Centro Hospitalar de Lisboa Norte EPE- Hospital Santa Maria | Lisboa | |
Portugal | Centro Hospitalar do Porto | Porto | |
Spain | Hospital Universitari Germans Trias i Pujol | Barcelona | |
Spain | Hospital Juan Ramón Jiménez | Huelva | |
Spain | Hospital Juan Ramón Jiménez | Huelva | |
Spain | Clinica Universidad de Navarra Madrid | Madrid | |
Spain | Hospital Universitario Puerta de Hierro | Madrid | |
Spain | Hospital Son Llàtzer | Palma De Mallorca | |
Spain | Clínica Universidad de Navarra | Pamplona | Navarra |
Spain | Hospital Clínico Universitario de Santiago de Compostela | Santiago De Compostela | |
Spain | Hospital Clínico Universitario de Valencia | Valencia | |
United Kingdom | Richmond Pharmacology | London | |
United Kingdom | Royal Free Hospital | London | England |
United States | Piedmont Heart Institute Athens | Athens | Georgia |
United States | Emory Heart and Vascular Center | Atlanta | Georgia |
United States | University of Colorado Hospital - Anschutz Medical Campus | Aurora | Colorado |
United States | MedStar Medical Group Cardiology at Franklin Square Medical Center | Baltimore | Maryland |
United States | Boston University School of Medicine | Boston | Massachusetts |
United States | Saint Elizabeth's Medical Center | Boston | Massachusetts |
United States | Montefiore Medical Center | Bronx | New York |
United States | University of North Carolina - Chapel Hill | Chapel Hill | North Carolina |
United States | The Medical University of South Carolina | Charleston | South Carolina |
United States | Northwestern University | Chicago | Illinois |
United States | The University of Chicago Medical Center | Chicago | Illinois |
United States | Cleveland Clinic | Cleveland | Ohio |
United States | University of Texas Southwestern Medical Center | Dallas | Texas |
United States | Duke University Health System | Durham | North Carolina |
United States | NorthShore University Health System | Evanston | Illinois |
United States | Prisma Health - Greenville Memorial Hospital | Greenville | South Carolina |
United States | Indiana University | Indianapolis | Indiana |
United States | Saint Luke's Hospital - Kansas City | Kansas City | Missouri |
United States | Cedars-Sinai Medical Center | Los Angeles | California |
United States | North Shore University Hospital | Manhasset | New York |
United States | University of Miami - Sylvester Comprehensive Cancer Center | Miami | Florida |
United States | Yale School of Medicine | New Haven | Connecticut |
United States | Columbia University Medical Center | New York | New York |
United States | Mount Sinai Hospital | New York | New York |
United States | New York University Langone Health | New York | New York |
United States | Newark Beth Israel Medical Center | Newark | New Jersey |
United States | Penn Presbyterian Medical Center | Philadelphia | Pennsylvania |
United States | Allegheny General Hospital | Pittsburgh | Pennsylvania |
United States | University of Pittsburgh | Pittsburgh | Pennsylvania |
United States | Oregon Health and Science University | Portland | Oregon |
United States | Virginia Commonwealth University Medical Center | Richmond | Virginia |
United States | Carilion Clinic Roanoke Heart Institute | Roanoke | Virginia |
United States | Mayo Clinic | Rochester | Minnesota |
United States | Laurelton Heart Specialist | Rosedale | New York |
United States | Washington University School of Medicine | Saint Louis | Missouri |
United States | University of Utah | Salt Lake City | Utah |
United States | Pacific Heart Institute | Santa Monica | California |
United States | University of Washington School of Medicine | Seattle | Washington |
United States | Providence Sacred Heart Medical Center | Spokane | Washington |
United States | MedStar Washington Hospital Center | Washington | District of Columbia |
Lead Sponsor | Collaborator |
---|---|
Eidos Therapeutics, a BridgeBio company |
United States, Australia, Belgium, Brazil, Canada, Czechia, Denmark, Greece, Ireland, Israel, Italy, Korea, Republic of, Netherlands, New Zealand, Poland, Portugal, Spain, United Kingdom,
Type | Measure | Description | Time frame | Safety issue |
---|---|---|---|---|
Other | Effects of acoramidis on circulating biomarker of myocardial wall stress | Changes in level of NT-proBNP | 12 months | |
Other | Effects of acoramidis on circulating biomarker of microvascular ischemia | Changes in level of Troponin I (TnI) | 12 months and 30 months | |
Other | Characterize PK of acoramidis | PK measures of acoramidis and its predominant metabolite after oral administration of acoramidis HCl 800 mg BID for steady state (every 3 months), in a subgroup of subjects followed at centers participating in the PK-PD substudy | 12 months and 30 months | |
Other | Evaluate effect of acoramidis on health-related quality of life questionnaire EuroQol EQ-5D-5L | Change from Baseline to Month 30 in the EQ-5D-5L score. EQ-5D-5L consists of 2 parts: EQ-5D descriptive system and EQ visual analogue scale (EQ VAS). EQ-5D comprises five dimensions: mobility, self-care, usual activities, pain or discomfort and anxiety or depression. Each dimension in EQ-5D-5L has five response levels of function: no problem (Level 1); slight problem (Level 2); moderate problem (Level 3); severe problem (Level 4); and extreme problem (Level 5). The subject is asked to indicate his health state by ticking the box next to the most appropriate statement in each of the five dimensions. The digits for the five dimensions can be combined into a 5-digit number, the utility score, that describes the subject's health state. A lower value indicates better perceived health state. On EQ VAS, the subject circles a single rating of self-perceived health on a 0 to 100 mm scale representing "the worst imaginable health state" and "the best imaginable health state", respectively. | 12 months and 30 months | |
Other | Assess acoramidis activity across TTR mutations | Acoramidis binding to or stabilization across a panel of TTR mutations by additional assays | 12 months and 30 months | |
Primary | 6-Minute Walk Test (6MWT) through Month 12 | Change from baseline to Month 12 of treatment in the total distance walked in 6 minutes | 12 months | |
Primary | A hierarchical combination of all-cause mortality, cumulative frequency of cardiovascular-related hospitalization, change from baseline in NT-proBNP, and change from baseline in 6MWT over a 30-month fixed treatment duration | Each subject will be compared to every other subject within a stratum over outcomes of all-cause mortality (death due to any cause), cumulative frequency of cardiovascular-related hospitalizations (number of times a subject is hospitalized for cardiovascular-related causes), change from baseline in NT-proBNP, and change from baseline in the total distance walked in 6 minutes (distance in meters).
The hierarchical approach with the Finkelstein-Schoenfeld test will be applied and the test recognizes the greater importance of the mortality endpoint. Scores are transformed to -1, 0, +1. The alternative hypothesis is a subject in the acoramidis treatment group will have a greater score than a subject in the placebo group. |
30 months | |
Secondary | Evaluate effects of acoramidis on quality of life (QoL) through Month 12 | Change from Baseline to Month 12 as measured in the Kansas City Cardiomyopathy Questionnaire Overall Summary score (KCCQ-OS). The KCCQ is a 23-item questionnaire developed to measure health status and health-related quality of life in subjects with heart failure. Items include heart failure symptoms, impact on physical and social functions, and how their heart failure impacts their quality of life (QoL). An Overall Summary score can be derived from the physical function, symptom (frequency and severity), social function and quality of life domains. For each domain, scores are transformed to a range of 0-100 using the formula, 100*[(mean of questions actually answered) - 1]/4, in which higher scores reflect better health status. The Overall Summary score is the mean of the domains scores, range from 0 to 100, in which higher scores reflect better health status. | 12 months | |
Secondary | Evaluate 6-Minute Walk Test (6MWT) through Month 30 | Change from baseline to Month 30 of treatment in the total distance walked in 6 minutes | 30 months | |
Secondary | Evaluate effects of acoramidis on quality of life (QoL) through Month 30 | Change from Baseline to Month 30 as measured in the Kansas City Cardiomyopathy Questionnaire Overall Summary score (KCCQ-OS). The KCCQ is a 23-item questionnaire developed to measure health status and health-related quality of life in subjects with heart failure. Items include heart failure symptoms, impact on physical and social functions, and how their heart failure impacts their quality of life (QoL). An Overall Summary score can be derived from the physical function, symptom (frequency and severity), social function and quality of life domains. For each domain, scores are transformed to a range of 0-100 using the formula, 100*[(mean of questions actually answered) - 1]/4, in which higher scores reflect better health status. The Overall Summary score is the mean of the domains scores, range from 0 to 100, in which higher scores reflect better health status. | 30 months | |
Secondary | Assess PD effects of circulating prealbumin by in vivo biomarker stabilization through Month 30 | Change from baseline to Month 30 in serum TTR (prealbumin) level (an in vivo measure of TTR stabilization) | 30 months | |
Secondary | Assess all-cause mortality | All-Cause Mortality by Month 30 including death due to any cause, heart transplant, or CMAD | 30 months | |
Secondary | Assess safety and tolerability through Month 12 | Safety parameters to be assessed: treatment- emergent serious adverse events (SAEs) and adverse events (AEs), AEs leading to treatment discontinuation, abnormal physical exam findings of clinical relevance, abnormal vital signs of clinical relevance, abnormal ECG parameters of clinical relevance, and changes in clinical safety laboratory parameters of potential clinical concern | 12 months | |
Secondary | PD assessments of TTR stabilization through Month 12 | Change from baseline in TTR (prealbumin) level (an in vivo measure of TTR stabilization) at Month 12
TTR stabilization as measured in established ex-vivo assays (fluorescent probe exclusion [FPE] and Western blot) at Month 12 in the PK-PD substudy |
12 months | |
Secondary | Efficacy by individual components and hierarchical combinations through Month 30 | A hierarchical combination of All-Cause mortality and cumulative frequency of CV-related hospitalization over a 30-month fixed treatment duration
A hierarchical combination of All-Cause mortality, cumulative frequency of CV-related hospitalization, and change from baseline in 6MWT over a 30-month fixed treatment duration Change in NT-proBNP from baseline to Month 30 of treatment Cumulative frequency of CV-related hospitalization by Month 30 |
30 months | |
Secondary | Efficacy of acoramidis in reducing CV mortality | Total number of deaths adjudicated as being related to cardiovascular causes | 30 months | |
Secondary | Incidence of treatment-emergent events | Assessment of incidence of treatment- emergent serious adverse events (SAEs) and adverse events (AEs) | 30 months |
Status | Clinical Trial | Phase | |
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