Efficacy and Safety of AG10 in Subjects With Transthyretin Amyloid Cardiomyopathy (ATTRibute-CM)

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)

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).

Study Overview

• Status: Completed
• Conditions: Heart Diseases; Amyloidosis; Cardiomyopathies; Transthyretin Amyloidosis; Amyloid Cardiomyopathy
• Intervention / Treatment: Drug: acoramidis; Drug: Placebo Oral Tablet

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.

• Study Type: Interventional
• Enrollment (Actual): 632
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • Adelaide, Australia
    • Royal Adelaide Hospital
  • Box Hill, Australia
    • Box Hill Hospital
  • Hobart, Australia
    • Royal Hobart Hospital
  • Murdoch, Australia
    • Fiona Stanley Hospital
  • Sydney, Australia, 2010
    • Saint Vincent's Hospital Sydney
  • Woolloongabba, Australia
    • Princess Alexandra Hospital
• Belgium
  • Aalst, Belgium
    • Onze-Lieve-vrouw Ziekenhuis Aalst
  • Leuven, Belgium
    • Universitair Ziekenhuis Leuven
  • Limburg
    • Genk, Limburg, Belgium
      • Ziekenhuis Oost-Limburg - Campus Sint-Jan
    • Hasselt, Limburg, Belgium
      • Jessa Ziekenhuis - Campus Virga Jesse
  • West Vlaanderen
    • Brugge, West Vlaanderen, Belgium
      • Algemeen Ziekenhuis Sint-Jan Brugge-Oostende
• Brazil
  • Porto Alegre, Brazil
    • Instituto de Cardiologia do Rio Grande do Sul
  • Bahia
    • Salvador, Bahia, Brazil
      • Hospital Cardio Pulmonar
  • Rio Grande Do Sul
    • Porto Alegre, Rio Grande Do Sul, Brazil, 90020-090
      • Santa Casa de Misericordia - Porto Alegre
  • Sao Paulo
    • Ribeirão Preto, Sao Paulo, Brazil, 14026-900
      • CAPED - Centro Avançado de Pesquisa e Estudos para o Diagnóstico
    • São Paulo, Sao Paulo, Brazil
      • InCor
• Canada
  • Montréal, Canada
    • Montreal Heart Institute
  • Alberta
    • Calgary, Alberta, Canada, T2N 4Z6
      • University of Calgary
  • British Columbia
    • Vancouver, British Columbia, Canada, V5Z 1M9
      • University of British Columbia
  • Manitoba
    • Winnipeg, Manitoba, Canada
      • CancerCare Manitoba - St. Boniface
  • Nova Scotia
    • Halifax, Nova Scotia, Canada, B3H 3A7
      • Halifax Infirmary
  • Ontario
    • Toronto, Ontario, Canada, M4P 1E4
      • Toronto Heart Centre
    • Toronto, Ontario, Canada, M5G 2N2
      • University of Toronto
  • Quebec
    • Montréal, Quebec, Canada, H4J 1C5
      • Hopital du Sacre-Coeur de Montreal
    • Montréal, Quebec, Canada, H2X 3H8
      • Centre Hospitalier de L'Universite de Montreal - Hôpital Notre-Dame
    • Quebec City, Quebec, Canada, G1V 4G5
      • Institut Universitaire De Cardiologie Et De Pneumologie De Québec
    • Rimouski, Quebec, Canada, G5L 5T1
      • Hôpital Regional de Rimouski
• Czechia
  • Brno Střed, Czechia
    • St. Anne´s University Hospital
  • Nové Město, Czechia
    • General University Hospital in Prague
  • Prague, Czechia
    • Institute for Clinical and Experimental Medicine
• Denmark
  • Dinamarca
    • Aarhus, Dinamarca, Denmark, 8200
      • Aarhus Universitetshospital
• Greece
  • Attica
    • Athens, Attica, Greece
      • Alexandra General Hospital of Athens
• Ireland
  • Dublin, Ireland
    • Mater Misericordiae University Hospital
  • Dublin, Ireland
    • Saint Vincents University Hospital
• Israel
  • Jerusalem, Israel
    • Hadassah University Hospital Ein Kerem
  • Tel Hashomer, Israel
    • The Chaim Sheba Medical Center
• Italy
  • Arezzo, Italy
    • Ospedale San Donato
  • Bologna, Italy
    • Azienda Ospedaliero Universitaria di Bologna Policlinico Sant'Orsola-Malpighi
  • Firenze, Italy
    • Azienda Ospedaliero - Universitaria Careggi
  • Pavia, Italy, 27100
    • Fondazione IRCCS Policlinico San Matteo
  • Pisa, Italy
    • Fondazione Toscana Gabriele Monasterio per la Ricerca Medica e di Sanita Pubblica
  • Rimini, Italy
    • Ospedale degli Infermi
  • Roma, Italy
    • Universita degli Studi di Roma La Sapienza - Umberto I Policlinico di Roma
• Korea, Republic of
  • Gyeonggi-Do
    • Seongnam-si, Gyeonggi-Do, Korea, Republic of, 13620
      • Seoul National University Bundang Hospital
    • Seoul, Gyeonggi-Do, Korea, Republic of, 13620
      • Seoul National University Hospital
• Netherlands
  • Groningen, Netherlands
    • Universitair Medisch Centrum Groningen
  • Utrecht, Netherlands
    • Universitair Medisch Centrum Utrecht
  • Limburg
    • Maastricht, Limburg, Netherlands, 6229 HX
      • Maastricht Universitair Medisch Centrum
• New Zealand
  • Auckland
    • Otahuhu, Auckland, New Zealand, 1640
      • Middlemore Hospital
  • Waikato
    • Hamilton, Waikato, New Zealand, 3240
      • Waikato Hospital
• Poland
  • Warsaw, Poland
    • National Institute of Cardiology
• Portugal
  • Lisboa, Portugal
    • Centro Hospitalar de Lisboa Norte EPE- Hospital Santa Maria
  • Porto, Portugal, 4099-001
    • Centro Hospitalar do Porto
• Spain
  • Barcelona, Spain
    • Hospital Universitari Germans Trias i Pujol
  • Huelva, Spain
    • Hospital Juan Ramon Jimenez
  • Huelva, Spain, 21005
    • Hospital Juan Ramon Jimenez
  • Madrid, Spain
    • Hospital Universitario Puerta de Hierro
  • Madrid, Spain
    • Clinica Universidad de Navarra Madrid
  • Palma De Mallorca, Spain
    • Hospital Son Llàtzer
  • Santiago De Compostela, Spain
    • Hospital Clínico Universitario de Santiago de Compostela
  • Valencia, Spain
    • Hospital Clínico Universitario de Valencia
  • Navarra
    • Pamplona, Navarra, Spain
      • Clinica Universidad de Navarra
• United Kingdom
  • London, United Kingdom, SE1 1YR
    • Richmond Pharmacology
  • England
    • London, England, United Kingdom, NW3 2PF
      • Royal Free Hospital
• United States
  • California
    • Los Angeles, California, United States, 90048
      • Cedars-Sinai Medical Center
    • Santa Monica, California, United States, 90404
      • Pacific Heart Institute
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado Hospital - Anschutz Medical Campus
  • Connecticut
    • New Haven, Connecticut, United States, 06473
      • Yale School of Medicine
  • District of Columbia
    • Washington, District of Columbia, United States, 20010
      • Medstar Washington Hospital Center
  • Florida
    • Miami, Florida, United States, 33136
      • University of Miami - Sylvester Comprehensive Cancer Center
  • Georgia
    • Athens, Georgia, United States, 30606
      • Piedmont Heart Institute Athens
    • Atlanta, Georgia, United States, 30322
      • Emory Heart and Vascular Center
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern University
    • Chicago, Illinois, United States, 60637
      • The University of Chicago Medical Center
    • Evanston, Illinois, United States, 60201
      • Northshore University Health System
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University
  • Maryland
    • Baltimore, Maryland, United States, 21218
      • MedStar Medical Group Cardiology at Franklin Square Medical Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02118
      • Boston University School of Medicine
    • Boston, Massachusetts, United States, 02135
      • Saint Elizabeth's Medical Center
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic
  • Missouri
    • Kansas City, Missouri, United States, 64111
      • Saint Luke's Hospital - Kansas City
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine
  • New Jersey
    • Newark, New Jersey, United States, 07112
      • Newark Beth Israel Medical Center
  • New York
    • Bronx, New York, United States, 10461
      • Montefiore Medical Center
    • Manhasset, New York, United States, 11030
      • North Shore University Hospital
    • New York, New York, United States, 10029
      • Mount Sinai Hospital
    • New York, New York, United States, 10010
      • New York University Langone Health
    • New York, New York, United States, 10034
      • Columbia University Medical Center
    • Rosedale, New York, United States, 11422
      • Laurelton Heart Specialist
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27514
      • University of North Carolina - Chapel Hill
    • Durham, North Carolina, United States, 27710
      • Duke University Health System
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health and Science University
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Penn Presbyterian Medical Center
    • Pittsburgh, Pennsylvania, United States, 15213
      • University of Pittsburgh
    • Pittsburgh, Pennsylvania, United States, 15212
      • Allegheny General Hospital
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • The Medical University of South Carolina
    • Greenville, South Carolina, United States, 29605
      • Prisma Health - Greenville Memorial Hospital
  • Texas
    • Dallas, Texas, United States, 75390
      • University of Texas Southwestern Medical Center
  • Utah
    • Salt Lake City, Utah, United States, 84132
      • University of Utah
  • Virginia
    • Richmond, Virginia, United States, 23298
      • Virginia Commonwealth University Medical Center
    • Roanoke, Virginia, United States, 24014
      • Carilion Clinic Roanoke Heart Institute
  • Washington
    • Seattle, Washington, United States, 98195
      • University of Washington School of Medicine
    • Spokane, Washington, United States, 99204
      • Providence Sacred Heart Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 90 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: acoramidis HCl 800 mg; 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.	Drug: acoramidis; TTR stabilizer administered orally twice daily (BID); Other Names: AG10; ALXN2060
Placebo Comparator: Placebo; 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.	Drug: Placebo Oral Tablet; Non-active control administered orally twice daily (BID)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	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.	Baseline up to Month 30

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline to Month 30 in the Distance Walked During the 6 Minute Walk Test (6MWT)	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.	Month 30
Change From Baseline to Month 30 of the Kansas City Cardiomyopathy Questionnaire Overall Score (KCCQ-OS)	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.	Month 30
Change From Baseline to Month 30 in Serum TTR (Prealbumin) Level	Serum TTR (Prealbumin) is an in vivo biomarker of stabilization.	Month 30
All-cause Mortality by Month 30, Including Death Due to Any Cause, Heart Transplant or Cardiac Mechanical Assist Device (CMAD)	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.	Baseline up to Month 30

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Effects of acoramidis on circulating biomarker of myocardial wall stress	Changes in level of NT-proBNP	12 months
Effects of acoramidis on circulating biomarker of microvascular ischemia	Changes in level of Troponin I (TnI)	12 months and 30 months
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
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
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

Collaborators and Investigators

• Sponsor: Eidos Therapeutics, a BridgeBio company

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): March 19, 2019
• Primary Completion (Actual): May 11, 2023
• Study Completion (Actual): May 11, 2023

Study Registration Dates

• First Submitted: February 27, 2019
• First Submitted That Met QC Criteria: February 28, 2019
• First Posted (Actual): March 4, 2019

Study Record Updates

• Last Update Posted (Actual): June 27, 2024
• Last Update Submitted That Met QC Criteria: June 5, 2024
• Last Verified: June 1, 2024

More Information

Terms related to this study

• Keywords: TTR; Amyloidosis; Transthyretin; Amyloid; ATTR-CM
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Metabolic Diseases; Proteostasis Deficiencies; Heart Diseases; Amyloidosis; Cardiomyopathies
• Other Study ID Numbers: AG10-301; 2018-004280-32 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No