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)

Transthyretin-Mediated Amyloid Cardiomyopathy (ATTR CM) Clinical Trial

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)

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT04136171
• Other study ID #: ION-682884-CS2
• Secondary ID: 2019-002835-27
• Status: Active, not recruiting
• Phase: Phase 3
• Start date: March 13, 2020
• Est. completion date: November 2025

Study information

• Verified date: January 2024
• Source: Ionis Pharmaceuticals, Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 1438
• Est. completion date: November 2025
• Est. primary completion date: June 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 90 Years

Eligibility

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.

Related Conditions & MeSH terms

• Amyloidosis
• Cardiomyopathies
• Transthyretin-Mediated Amyloid Cardiomyopathy (ATTR CM)

Intervention

Drug:
• Eplontersen
Eplontersen by subcutaneous injection
• Placebo
Eplontersen-matching placebo by subcutaneous injection

Locations

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

Sponsors (1)

Lead Sponsor	Collaborator
Ionis Pharmaceuticals, Inc.

Countries where clinical trial is conducted

United States,  Argentina,  Australia,  Austria,  Belgium,  Brazil,  Canada,  Czechia,  Denmark,  France,  Germany,  Greece,  Israel,  Italy,  Japan,  Poland,  Portugal,  Puerto Rico,  Spain,  Sweden,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Composite Outcome of Cardiovascular (CV) Mortality and Recurrent CV Clinical Events up to Week 140		Baseline up to Week 140
Secondary	Change From Baseline in the 6-minute Walk Test (6MWT) Distance at Week 121	The 6MWT is a submaximal exercise test that entails measurement of distance walked over a span of 6 minutes. The 6MWT provides information regarding functional capacity, response to therapy and prognosis across a range of chronic cardiopulmonary conditions.	Baseline to Week 121
Secondary	Change From Baseline in the Kansas City Cardiomyopathy Questionnaire (KCCQ) Scores at Week 121	The Kansas City Cardiomyopathy Questionnaire (KCCQ) is a 23-item self-administered questionnaire developed to independently measure the participant's perception of their health status, which includes heart failure symptoms, impact on physical and social function, and how their heart failure impacts their quality of life (QOL) within a 2-week recall period.; The KCCQ tool quantifies the following six (6) distinct domains and two (2) summary scores. KCCQ responses are provided along a rating scale continuum with equal spacing from worst to best, with a higher score equaling a better score.	Baseline to Week 121
Secondary	CV Clinical Events up to Week 140		Baseline up to Week 140
Secondary	CV Mortality up to Week 140		Baseline up to Week 140
Secondary	All-Cause Mortality up to Week 140		Baseline up to Week 140

External Links

•   CARDIO-TTRansform Website