Efficacy and Safety of AG10 in Subjects With Transthyretin Amyloid Cardiomyopathy

Heart Diseases Clinical Trial

— ATTRibute-CM  

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)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03860935
• Other study ID #: AG10-301
• Secondary ID: 2018-004280-32
• Status: Completed
• Phase: Phase 3
• Start date: March 19, 2019
• Est. completion date: May 11, 2023

Study information

• Verified date: July 2023
• Source: Eidos Therapeutics, a BridgeBio company
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

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 information / eligibility

• 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

Related Conditions & MeSH terms

• Amyloid Cardiomyopathy
• Amyloidosis
• Cardiomyopathies
• Heart Diseases
• Transthyretin Amyloidosis

Intervention

Drug:
• acoramidis
TTR stabilizer administered orally twice daily (BID)
• Placebo Oral Tablet
Non-active control administered orally twice daily (BID)

Locations

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

Sponsors (1)

Lead Sponsor	Collaborator
Eidos Therapeutics, a BridgeBio company

Countries where clinical trial is conducted

United States,  Australia,  Belgium,  Brazil,  Canada,  Czechia,  Denmark,  Greece,  Ireland,  Israel,  Italy,  Korea, Republic of,  Netherlands,  New Zealand,  Poland,  Portugal,  Spain,  United Kingdom, 

Outcome

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