Clinical trial NCT04136171: CARDIO-TTRansform: A Study to Evaluate the Efficacy and Safety of Eplontersen (Formerly Known as ION-682884, IONIS-TTR-LRx and AKCEA-TTR-LRx) in Participants With Transthyretin-Mediated Amyloid Cardiomyopathy (ATTR CM)
Official title: A Phase 3 Global, Double-Blind, Randomized, Placebo-Controlled Study to Evaluate the Efficacy and Safety of ION-682884 in Patients With Transthyretin-Mediated Amyloid Cardiomyopathy (ATTR CM)
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Transthyretin-Mediated Amyloid Cardiomyopathy (ATTR CM)
Keywords: TTR
Amyloidosis
Cardiomyopathy
Lead sponsor: Ionis Pharmaceuticals, Inc.
Sponsor class: INDUSTRY
First posted: 2019-10-23
Enrollment: 1438
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: To evaluate the efficacy of eplontersen compared to placebo in participants with ATTR-CM receiving available standard of care (SoC). For more information, please visit https://www.cardio-ttransform.com.

Detailed description: This is a multicenter, double-blind study in approximately 1400 participants, who will be randomized to receive subcutaneous (SC) injections of either eplontersen or placebo once every 4 weeks. Participants will also receive daily supplemental doses of the recommended daily allowance of vitamin A.

Eligibility criteria: Inclusion Criteria:

* Females must be non-pregnant and non-lactating, and either surgically sterile or post-menopausal or abstinent. If engaged in sexual relations of child-bearing potential, agree to use 1 highly effective contraceptive method
* Males must be surgically sterile or, abstinent or, if engaged in sexual relations with a woman of child-bearing potential, the participant or the participant's non-pregnant female partner must be using a highly effective contraceptive method
* Amyloid deposits in cardiac or non-cardiac tissue confirmed by Congo Red (or equivalent) staining OR technetium scintigraphy (99mTc -3,3-diphosphono-1,2- propanodicarboxylic acid \[DPD-Tc\], 99m Tc-pyrophosphate \[PYP-Tc\], or 99m Tc-hydroxymethylene-diphosphonate \[HMDP-Tc\]) with Grade 2 or 3 cardiac uptake in the absence of abnormal light chains ratio, centrally confirmed
* End-diastolic interventricular septum thickness of \> 12 millimeters (mm) on Screening echocardiogram
* New York Heart Association (NYHA) class I-III

Exclusion Criteria:

* Acute coronary syndrome, unstable angina, stroke, transient ischemic attack (TIA), coronary revascularization, cardiac device implantation, cardiac valve repair, or major surgery within 3 months of Screening
* Cardiomyopathy not primarily caused by ATTR-CM, for example, cardiomyopathy due to hypertension, valvular heart disease, or ischemic heart disease
* Monoclonal gammopathy of undetermined significance (MGUS) and/or alterations in immunoglobulin free light chain (FLC) ratio unless fat, bone marrow, or heart biopsy confirming the absence of light chain and the presence of TTR protein by mass spectrometry or immunoelectron microscopy. For participants with chronic kidney disease (CKD) and without presence of monoclonal protein in blood and urine, the acceptable FLC ratio is 0.26-2.25. Results different from that may be discussed with local hematologist, Investigator and Medical Monitor if the risks associated with the biopsy outweigh the benefits
* Prior liver or heart transplant, and/or Left Ventricular Assist Device (LVAD) or anticipated liver transplant or LVAD within 1 year after randomization
* Current or previous treatment with Tegsedi™ (inotersen) or Onpattro™ (patisiran) or other oligonucleotide or ribonucleic acid (RNA) therapeutic (including small interfering ribonucleic acid \[siRNA\]; does not apply to COVID-19 mitochondrial \[mRNA\] vaccinations)
* Current treatment with diflunisal, doxycycline, with or without ursodeoxycholic acid, and/or non-dihydropyridine calcium-channel blocker (e.g., verapamil, diltiazem). Participants receiving any of these agents must respect a wash-out period of 14 days before randomization.

Primary outcomes:
measure: Composite Outcome of Cardiovascular (CV) Mortality and Recurrent CV Clinical Events up to Week 140
timeFrame: Baseline up to Week 140
Secondary outcomes:
measure: Change From Baseline in the 6-minute Walk Test (6MWT) Distance at Week 121
timeFrame: Baseline to Week 121
measure: Change From Baseline in the Kansas City Cardiomyopathy Questionnaire (KCCQ) Scores at Week 121
timeFrame: Baseline to Week 121
measure: CV Clinical Events up to Week 140
timeFrame: Baseline up to Week 140
measure: CV Mortality up to Week 140
timeFrame: Baseline up to Week 140
measure: All-Cause Mortality up to Week 140
timeFrame: Baseline up to Week 140
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: Mayo Clinic - Arizona
state: Arizona
city: La Jolla
country: United States
facility: Altman Clinical and Translational Research Institute Center for Clinical Research
state: California
city: Los Angeles
country: United States
facility: Cedars-Sinai Medical Center
state: California
city: San Francisco
country: United States
facility: University of California, San Francisco (UCSF) - Medical Center
state: California
city: Stanford
country: United States
facility: Stanford Hospital
state: California
city: Aurora
country: United States
facility: University of Colorado Hospital - Anschutz Medical Campus
state: Colorado
city: Washington
country: United States
facility: MedStar Washington Hospital Center
state: District of Columbia
city: Washington
country: United States
facility: The George Washington Medical Faculty Associates - Foggy Bottom North Pavilion
state: District of Columbia
city: Weston
country: United States
facility: Cleveland Clinic Florida
state: Florida
city: Atlanta
country: United States
facility: Emory Heart and Vascular Center - Emory Clifton Campus
state: Georgia
city: Fayetteville
country: United States
facility: Piedmont Heart of Fayetteville
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: Maywood
country: United States
facility: Loyola University Medical Center
state: Illinois
city: Indianapolis
country: United States
facility: Indiana University Health
state: Indiana
city: Kansas City
country: United States
facility: University of Kansas Medical Center
state: Kansas
city: New Orleans
country: United States
facility: Louisiana State University Health Sciences Center
state: Louisiana
city: New Orleans
country: United States
facility: Tulane University Heart and Vascular Institute
state: Louisiana
city: New Orleans
country: United States
facility: Ochsner Health System
state: Louisiana
city: Baltimore
country: United States
facility: University of Maryland Medical Center
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Boston
country: United States
facility: Brigham and Women's Hospital
state: Massachusetts
city: Boston
country: United States
facility: Boston University School of Medicine
state: Massachusetts
city: Detroit
country: United States
facility: Henry Ford Health System
state: Michigan
city: Minneapolis
country: United States
facility: Minneapolis Heart Institute
state: Minnesota
city: Rochester
country: United States
facility: Mayo Clinic - Rochester
state: Minnesota
city: Kansas City
country: United States
facility: Saint Luke's Hospital of Kansas City
state: Missouri
city: Saint Louis
country: United States
facility: Barnes-Jewish Hospital
state: Missouri
city: New York
country: United States
facility: New York University Langone Cardiology Associates
state: New York
city: New York
country: United States
facility: Columbia University Irving Medical Center
state: New York
city: New York
country: United States
facility: Weill Cornell Medicine Cardiology
state: New York
city: Rosedale
country: United States
facility: Laurelton Heart Specialists
state: New York
city: Chapel Hill
country: United States
facility: The University of North Carolina at Chapel Hill
state: North Carolina
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Cincinnati
country: United States
facility: Carl and Edyth Lindner Research Center at The Christ Hospital
state: Ohio
city: Cleveland
country: United States
facility: University Hospitals Cleveland Medical Center
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic Main Campus
state: Ohio
city: Columbus
country: United States
facility: The Ohio State University College of Medicine
state: Ohio
city: Portland
country: United States
facility: Oregon Health and Science University
state: Oregon
city: Lancaster
country: United States
facility: Lancaster General Hospital
state: Pennsylvania
city: Philadelphia
country: United States
facility: Penn Presbyterian Medical Center
state: Pennsylvania
city: Pittsburgh
country: United States
facility: University of Pittsburgh Medical School
state: Pennsylvania
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
city: Dallas
country: United States
facility: University of Texas Southwestern Medical Center
state: Texas
city: Houston
country: United States
facility: Houston Methodist Hospital
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah
state: Utah
city: Richmond
country: United States
facility: Virginia Commonwealth University (VCU)
state: Virginia
city: Seattle
country: United States
facility: University of Washington
state: Washington
city: Madison
country: United States
facility: University of Wisconsin - Madison
state: Wisconsin
city: Milwaukee
country: United States
facility: Froedtert & Medical College of Wisconsin
state: Wisconsin
city: Ciudad Autonoma de Buenos Aires
country: Argentina
facility: Instituto Cardiovascular de Buenos Aires
state: Buenos Aires
city: Ciudad Autónoma De Buenos Aires
country: Argentina
facility: Hospital Italiano de Buenos Aires
state: Buenos Aires
city: Liverpool
country: Australia
facility: Liverpool Hospital
state: New South Wales
city: Westmead
country: Australia
facility: The Westmead Institute for Medical Research
state: New South Wales
city: Woolloongabba
country: Australia
facility: Princess Alexandra Hospital
state: Queensland
city: Leabrook
country: Australia
facility: Advara Heartcare
state: South Australia
city: Hobart
country: Australia
facility: Royal Hobart Hospital
state: Tasmania
city: Box Hill
country: Australia
facility: Box Hill Hospital
state: Victoria
city: Murdoch
country: Australia
facility: Advara HeartCare Murdoch
state: West Australia
city: Murdoch
country: Australia
facility: GenesisCare Murdoch
state: West Australia
city: Joondalup
country: Australia
facility: Advara HeartCare
state: Western Australia
city: Joondalup
country: Australia
facility: GenesisCare Joondalup
state: Western Australia
city: Graz
country: Austria
facility: Medizinische Universität Graz
state: Styria
city: Innsbruck
country: Austria
facility: Medizinische Universität Innsbruck
state: Tyrol
city: Vienna
country: Austria
facility: Medizinische Universität Wien
city: Genk
country: Belgium
facility: Ziekenhuis Oost-Limburg - Campus Sint-Jan
state: Limburg
city: Brugge
country: Belgium
facility: Algemeen Ziekenhuis Sint-Jan Brugge-Oostende - Campus Sint-Jan
state: West-Vlaanderen
city: Campinas
country: Brazil
facility: Universidade Estadual de Campinas
city: Porto Alegre
country: Brazil
facility: Hospital Moinhos de Vento
city: Ribeirão Preto
country: Brazil
facility: Centro Avançado de Pesquisa e Estudos para o Diagnóstico CAPED
city: Ribeirão Preto
country: Brazil
facility: Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto
city: São Paulo
country: Brazil
facility: A Beneficência Portuguesa de São Paulo - Unidade Mirante
city: São Paulo
country: Brazil
facility: Instituto Dante Pazzanese de Cardiologia
city: São Paulo
country: Brazil
facility: Instituto do Coração de São Paulo
city: Calgary
country: Canada
facility: University of Calgary
state: Alberta
city: Vancouver
country: Canada
facility: Gordon and Leslie Diamond Health Care Centre
state: British Columbia
city: London
country: Canada
facility: University Hospital - London Health Sciences Centre
state: Ontario
city: Toronto
country: Canada
facility: Toronto General Hospital
state: Ontario
city: Montréal
country: Canada
facility: Centre Hospitalier de l'Université de Montréal (CHUM)
state: Quebec
city: Rimouski
country: Canada
facility: Hôpital Regional de Rimouski
state: Quebec
city: Brno
country: Czechia
facility: Fakultní Nemocnice u sv. Anny v Brn
state: South Moravian
city: Prague
country: Czechia
facility: Vseobecna Fakultni Nemocnice v Praze
city: Prague
country: Czechia
facility: Institut Klinické a Experimentální Medicíny
city: Copenhagen
country: Denmark
facility: Rigshospitalet
state: Hovedstaden
city: Odense
country: Denmark
facility: Odense Universitetshospital
state: Syddanmark
city: Toulouse
country: France
facility: Hôpital Rangueil
state: Occitanie
city: Créteil
country: France
facility: Hôpitaux Universitaires Henri Mondor
city: La Roche-sur-Yon
country: France
facility: Centre Hospitalier Départemental Vendée
city: Marseille
country: France
facility: Hôpital de la Timone
city: Pessac
country: France
facility: Hôpital Haut-Lévêque
city: Saint-Herblain
country: France
facility: Centre Hospitalier Universitaire De Nantes - Hôpital Nord Laennec
city: Homburg
country: Germany
facility: Universitätsklinikum des Saarlandes
state: Saarland
city: Berlin
country: Germany
facility: Charité Campus Mitte
city: Berlin
country: Germany
facility: Charité Universitätsmedizin Berlin
city: Heidelberg
country: Germany
facility: Universitaetsklinikum Heidelberg - Zentrum fur Innere Medizin
city: Köln
country: Germany
facility: Uniklinik Koln
city: Münster
country: Germany
facility: Universitätsklinikum Münster
city: Würzburg
country: Germany
facility: Universitätsklinikum Würzburg
city: Athens
country: Greece
facility: Alexandra General Hospital
city: Haifa
country: Israel
facility: Rambam Health Care Campus
city: Jerusalem
country: Israel
facility: Hadassah University Hospital Ein Kerem
city: Rehovot
country: Israel
facility: Kaplan Medical Center
city: Ancona
country: Italy
facility: Azienda Ospedaliero Universitaria Ospedali Riuniti di Ancona
city: Bologna
country: Italy
facility: Azienda Ospedaliero-Universitaria di Bologna Policlinico Sant Orsola-Malpighi
city: Florence
country: Italy
facility: Azienda Ospedaliero - Universitaria Careggi
city: Padua
country: Italy
facility: Azienda Ospedale - Università di Padova
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 Sanita Pubblica
city: Roma
country: Italy
facility: Azienda Ospedaliera - Universitaria Sant' Andrea
city: Uwajima-shi
country: Japan
facility: Uwajima City Hospital
state: Ehime
city: Kitakyushu-shi
country: Japan
facility: Hospital of the University of Occupational and Environmental Health
state: Fukuoka
city: Kurume-shi
country: Japan
facility: Kurume University Hospital
state: Fukuoka
city: Sapporo-shi
country: Japan
facility: Sapporo Medical University Hospital
state: Hokkaido
city: Fukuoka
country: Japan
facility: Saiseikai Fukuoka General Hospital
state: Hukuoka
city: Kitakyushu
country: Japan
facility: Kokura Memorial Hospital
state: Hukuoka
city: Kyoto-shi
country: Japan
facility: University Hospital Kyoto Prefectural University of Medicine
state: Kyoto
city: Matsumoto
country: Japan
facility: Shinshu University Hospital
state: Nagano
city: Okayama-shi,
country: Japan
facility: Okayama University Hospital
state: Okayama
city: Osaka-shi
country: Japan
facility: Osaka Metropolitan University Hospital
state: Osaka
city: Hamamatsu
country: Japan
facility: Hamamatsu University Hospital
state: Shizuoka
city: Shinjuku-Ku
country: Japan
facility: Keio University Hospital
state: Tokyo
city: Kumamoto
country: Japan
facility: Kumamoto University Hospital
city: Kraków
country: Poland
facility: Krakowski Szpital Specjalistyczny im. Jana Pawa II
city: Warszawa
country: Poland
facility: Narodowy Instytut Kardiologii Stefana kardyna Wyszyskiego - Pastwowy Instytut Badawczy
city: Guimarães
country: Portugal
facility: Hospital da Senhora da Oliveira - Guimarães
city: Lisbon
country: Portugal
facility: Centro Hospitalar Universitário de Lisboa Central - Hospital de Santa Marta
city: Porto
country: Portugal
facility: Centro Hospitalar Universitário do Porto - Hospital Geral de Santo Antonio
city: Porto
country: Portugal
facility: Centro Hospitalar Universitário de São João
city: San Juan
country: Puerto Rico
facility: Veterans Affairs Caribbean Healthcare System
city: Barcelona
country: Spain
facility: Hospital Universitari Vall d'Hebrón
city: Majadahonda
country: Spain
facility: Hospital Universitario Puerta de Hierro - Majadahonda
city: Murcia
country: Spain
facility: Hospital Clínico Universitario Virgen de la Arrixaca
city: Santiago de Compostela
country: Spain
facility: Complejo Hospitalario Universitario de Santiago
city: Göteborg
country: Sweden
facility: Sahlgrenska Universitetssjukhuset
city: Skellefteå
country: Sweden
facility: Skellefteå lasarett
city: Glasgow
country: United Kingdom
facility: Synexus - Scotland Clinical Research Centre
state: Scotland
city: Cardiff
country: United Kingdom
facility: Synexus - Wales
state: Wales
city: Edgbaston
country: United Kingdom
facility: Synexus Midlands Clinical Research Centre
city: Hexham
country: United Kingdom
facility: Synexus - North Tees Clinical Research Centre
city: Liverpool
country: United Kingdom
facility: Synexus - Manchester Clinical Research Centre
city: Liverpool
country: United Kingdom
facility: Synexus - Merseyside Clinical Research Centre
city: London
country: United Kingdom
facility: Royal Free London NHS Foundation Trust
city: London
country: United Kingdom
facility: Richmond Pharmacology
Study officials:
References: