Clinical trial NCT03860935: Efficacy and Safety of AG10 in Subjects With Transthyretin Amyloid Cardiomyopathy
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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Amyloidosis
Amyloid Cardiomyopathy
Transthyretin Amyloidosis
Cardiomyopathies
Heart Diseases
Keywords: Amyloidosis
ATTR-CM
Transthyretin
Amyloid
TTR
Lead sponsor: Eidos Therapeutics, a BridgeBio company
Sponsor class: INDUSTRY
First posted: 2019-03-04
Enrollment: 632
Sex: ALL
Minimum age (years): 18
Maximum age (years): 90
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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

Primary outcomes:
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.
timeFrame: Baseline up to Month 30
Secondary outcomes:
measure: Change From Baseline to Month 30 in the Distance Walked During the 6 Minute Walk Test (6MWT)
timeFrame: Month 30
measure: Change From Baseline to Month 30 of the Kansas City Cardiomyopathy Questionnaire Overall Score (KCCQ-OS)
timeFrame: Month 30
measure: Change From Baseline to Month 30 in Serum TTR (Prealbumin) Level
timeFrame: Month 30
measure: All-cause Mortality by Month 30, Including Death Due to Any Cause, Heart Transplant or Cardiac Mechanical Assist Device (CMAD)
timeFrame: Baseline up to Month 30
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Cedars-Sinai Medical Center
state: California
city: Santa Monica
country: United States
facility: Pacific Heart Institute
state: California
city: Aurora
country: United States
facility: University of Colorado Hospital - Anschutz Medical Campus
state: Colorado
city: New Haven
country: United States
facility: Yale School of Medicine
state: Connecticut
city: Washington
country: United States
facility: MedStar Washington Hospital Center
state: District of Columbia
city: Miami
country: United States
facility: University of Miami - Sylvester Comprehensive Cancer Center
state: Florida
city: Athens
country: United States
facility: Piedmont Heart Institute Athens
state: Georgia
city: Atlanta
country: United States
facility: Emory Heart and Vascular Center
state: Georgia
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Chicago
country: United States
facility: The University of Chicago Medical Center
state: Illinois
city: Evanston
country: United States
facility: NorthShore University Health System
state: Illinois
city: Indianapolis
country: United States
facility: Indiana University
state: Indiana
city: Baltimore
country: United States
facility: MedStar Medical Group Cardiology at Franklin Square Medical Center
state: Maryland
city: Boston
country: United States
facility: Boston University School of Medicine
state: Massachusetts
city: Boston
country: United States
facility: Saint Elizabeth's Medical Center
state: Massachusetts
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Kansas City
country: United States
facility: Saint Luke's Hospital - Kansas City
state: Missouri
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Newark
country: United States
facility: Newark Beth Israel Medical Center
state: New Jersey
city: Bronx
country: United States
facility: Montefiore Medical Center
state: New York
city: Manhasset
country: United States
facility: North Shore University Hospital
state: New York
city: New York
country: United States
facility: New York University Langone Health
state: New York
city: New York
country: United States
facility: Mount Sinai Hospital
state: New York
city: New York
country: United States
facility: Columbia University Medical Center
state: New York
city: Rosedale
country: United States
facility: Laurelton Heart Specialist
state: New York
city: Chapel Hill
country: United States
facility: University of North Carolina - Chapel Hill
state: North Carolina
city: Durham
country: United States
facility: Duke University Health System
state: North Carolina
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
city: Portland
country: United States
facility: Oregon Health and Science University
state: Oregon
city: Philadelphia
country: United States
facility: Penn Presbyterian Medical Center
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Allegheny General Hospital
state: Pennsylvania
city: Pittsburgh
country: United States
facility: University of Pittsburgh
state: Pennsylvania
city: Charleston
country: United States
facility: The Medical University of South Carolina
state: South Carolina
city: Greenville
country: United States
facility: Prisma Health - Greenville Memorial Hospital
state: South Carolina
city: Dallas
country: United States
facility: University of Texas Southwestern Medical Center
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah
state: Utah
city: Richmond
country: United States
facility: Virginia Commonwealth University Medical Center
state: Virginia
city: Roanoke
country: United States
facility: Carilion Clinic Roanoke Heart Institute
state: Virginia
city: Seattle
country: United States
facility: University of Washington School of Medicine
state: Washington
city: Spokane
country: United States
facility: Providence Sacred Heart Medical Center
state: Washington
city: Adelaide
country: Australia
facility: Royal Adelaide Hospital
city: Box Hill
country: Australia
facility: Box Hill Hospital
city: Hobart
country: Australia
facility: Royal Hobart Hospital
city: Murdoch
country: Australia
facility: Fiona Stanley Hospital
city: Sydney
country: Australia
facility: Saint Vincent's Hospital Sydney
city: Woolloongabba
country: Australia
facility: Princess Alexandra Hospital
city: Genk
country: Belgium
facility: Ziekenhuis Oost-Limburg - Campus Sint-Jan
state: Limburg
city: Hasselt
country: Belgium
facility: Jessa Ziekenhuis - Campus Virga Jesse
state: Limburg
city: Brugge
country: Belgium
facility: Algemeen Ziekenhuis Sint-Jan Brugge-Oostende
state: West Vlaanderen
city: Aalst
country: Belgium
facility: Onze-Lieve-Vrouw Ziekenhuis Aalst
city: Leuven
country: Belgium
facility: Universitair Ziekenhuis Leuven
city: Salvador
country: Brazil
facility: Hospital Cárdio Pulmonar
state: Bahia
city: Porto Alegre
country: Brazil
facility: Santa Casa de Misericordia - Porto Alegre
state: Rio Grande Do Sul
city: Ribeirão Preto
country: Brazil
facility: CAPED - Centro Avançado de Pesquisa e Estudos para o Diagnóstico
state: Sao Paulo
city: São Paulo
country: Brazil
facility: INCOR
state: Sao Paulo
city: Porto Alegre
country: Brazil
facility: Instituto de Cardiologia do Rio Grande do Sul
city: Calgary
country: Canada
facility: University of Calgary
state: Alberta
city: Vancouver
country: Canada
facility: University of British Columbia
state: British Columbia
city: Winnipeg
country: Canada
facility: CancerCare Manitoba - St. Boniface
state: Manitoba
city: Halifax
country: Canada
facility: Halifax Infirmary
state: Nova Scotia
city: Toronto
country: Canada
facility: Toronto Heart Centre
state: Ontario
city: Toronto
country: Canada
facility: University of Toronto
state: Ontario
city: Montréal
country: Canada
facility: Centre Hospitalier de L'Universite de Montreal - Hôpital Notre-Dame
state: Quebec
city: Montréal
country: Canada
facility: Hôpital du Sacré-Coeur de Montréal
state: Quebec
city: Quebec City
country: Canada
facility: Institut Universitaire de Cardiologie et de Pneumologie de Québec
state: Quebec
city: Rimouski
country: Canada
facility: Hôpital régional de Rimouski
state: Quebec
city: Montréal
country: Canada
facility: Montreal Heart Institute
city: Brno Střed
country: Czechia
facility: St. Anne´s University Hospital
city: Nové Město
country: Czechia
facility: General University Hospital in Prague
city: Prague
country: Czechia
facility: Institute for Clinical and Experimental Medicine
city: Aarhus
country: Denmark
facility: Aarhus Universitetshospital
state: Dinamarca
city: Athens
country: Greece
facility: Alexandra General Hospital of Athens
state: Attica
city: Dublin
country: Ireland
facility: Mater Misericordiae University Hospital
city: Dublin
country: Ireland
facility: Saint Vincents University Hospital
city: Jerusalem
country: Israel
facility: Hadassah University Hospital Ein Kerem
city: Tel Hashomer
country: Israel
facility: The Chaim Sheba Medical Center
city: Arezzo
country: Italy
facility: Ospedale San Donato
city: Bologna
country: Italy
facility: Azienda Ospedaliero Universitaria di Bologna Policlinico Sant'Orsola-Malpighi
city: Firenze
country: Italy
facility: Azienda Ospedaliero - Universitaria Careggi
city: Pavia
country: Italy
facility: Fondazione IRCCS Policlinico San Matteo
city: Pisa
country: Italy
facility: Fondazione Toscana Gabriele Monasterio per la Ricerca Medica e di Sanità Pubblica
city: Rimini
country: Italy
facility: Ospedale degli Infermi
city: Roma
country: Italy
facility: Universita degli Studi di Roma La Sapienza - Umberto I Policlinico di Roma
city: Seongnam-si
country: Korea, Republic of
facility: Seoul National University Bundang Hospital
state: Gyeonggi-Do
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
state: Gyeonggi-Do
city: Maastricht
country: Netherlands
facility: Maastricht Universitair Medisch Centrum
state: Limburg
city: Groningen
country: Netherlands
facility: Universitair Medisch Centrum Groningen
city: Utrecht
country: Netherlands
facility: Universitair Medisch Centrum Utrecht
city: Otahuhu
country: New Zealand
facility: Middlemore Hospital
state: Auckland
city: Hamilton
country: New Zealand
facility: Waikato Hospital
state: Waikato
city: Warsaw
country: Poland
facility: National Institute of Cardiology
city: Lisboa
country: Portugal
facility: Centro Hospitalar de Lisboa Norte EPE- Hospital Santa Maria
city: Porto
country: Portugal
facility: Centro Hospitalar do Porto
city: Pamplona
country: Spain
facility: Clínica Universidad de Navarra
state: Navarra
city: Barcelona
country: Spain
facility: Hospital Universitari Germans Trias i Pujol
city: Huelva
country: Spain
facility: Hospital Juan Ramón Jiménez
city: Huelva
country: Spain
facility: Hospital Juan Ramón Jiménez
city: Madrid
country: Spain
facility: Clinica Universidad de Navarra Madrid
city: Madrid
country: Spain
facility: Hospital Universitario Puerta de Hierro
city: Palma De Mallorca
country: Spain
facility: Hospital Son Llàtzer
city: Santiago De Compostela
country: Spain
facility: Hospital Clínico Universitario de Santiago de Compostela
city: Valencia
country: Spain
facility: Hospital Clínico Universitario de Valencia
city: London
country: United Kingdom
facility: Royal Free Hospital
state: England
city: London
country: United Kingdom
facility: Richmond Pharmacology
Study officials:
References:
citation: Stern LK, Kittleson MM. Updates in Cardiac Amyloidosis Diagnosis and Treatment. Curr Oncol Rep. 2021 Mar 16;23(4):47. doi: 10.1007/s11912-021-01028-8.