Transthyretin-Mediated Amyloid Cardiomyopathy (ATTR CM)Phase 3NCT04136171
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)
A Phase 3 study testing Eplontersen in people with Transthyretin-Mediated Amyloid Cardiomyopathy (ATTR CM), run by Ionis Pharmaceuticals, Inc. at 139 sites in 21 countries.
Trial summary
To evaluate the efficacy of eplontersen compared to placebo in participants with ATTR-CM receiving available standard of care (SoC). Read more about this study
- Who is it for?
- Ages 18 to 90 years
- Conditions the study is for
- Transthyretin-Mediated Amyloid Cardiomyopathy (ATTR CM)
- What is being tested?
- Eplontersen
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 1,438 participants
- Where
- 139 sitesin 21 countries
- Study dates
- 13 Mar 2020to 12 Aug 2026
- Phase
- Phase 3
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 90 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Who cannot join
- 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.
Trial locations and contacts
139 sites in 21 countries.
139 sites in 21 countries
United States51 sites
Piedmont Heart of Fayetteville
Atlanta, Georgia, 30309
Emory Heart and Vascular Center - Emory Clifton Campus
Atlanta, Georgia, 30322
University of Colorado Hospital - Anschutz Medical Campus
Aurora, Colorado, 80045
University of Maryland Medical Center
Baltimore, Maryland, 21201
Massachusetts General Hospital
Boston, Massachusetts, 02114
Brigham and Women's Hospital
Boston, Massachusetts, 02115
Boston University School of Medicine
Boston, Massachusetts, 02118
The University of North Carolina at Chapel Hill
Chapel Hill, North Carolina, 27599
Medical University of South Carolina
Charleston, South Carolina, 29425
Northwestern University
Chicago, Illinois, 60611
The University of Chicago Medical Center
Chicago, Illinois, 60637
Carl and Edyth Lindner Research Center at The Christ Hospital
Cincinnati, Ohio, 45219
University Hospitals Cleveland Medical Center
Cleveland, Ohio, 44106
Cleveland Clinic Main Campus
Cleveland, Ohio, 44195
The Ohio State University College of Medicine
Columbus, Ohio, 43210
University of Texas Southwestern Medical Center
Dallas, Texas, 75390
Henry Ford Health System
Detroit, Michigan, 48202
Duke University Medical Center
Durham, North Carolina, 27710
Piedmont Heart of Fayetteville
Fayetteville, Georgia, 30214
Houston Methodist Hospital
Houston, Texas, 77030
Indiana University Health
Indianapolis, Indiana, 46202
University of Kansas Medical Center
Kansas City, Kansas, 66160
Saint Luke's Hospital of Kansas City
Kansas City, Missouri, 64111
Altman Clinical and Translational Research Institute Center for Clinical Research
La Jolla, California, 92037
Lancaster General Hospital
Lancaster, Pennsylvania, 17602
Cedars-Sinai Medical Center
Los Angeles, California, 90048
University of Wisconsin - Madison
Madison, Wisconsin, 53792
Loyola University Medical Center
Maywood, Illinois, 60153
Froedtert & Medical College of Wisconsin
Milwaukee, Wisconsin, 53226
Minneapolis Heart Institute
Minneapolis, Minnesota, 55407
Vanderbilt University Medical Center
Nashville, Tennessee, 37232
Tulane University Heart and Vascular Institute
New Orleans, Louisiana, 70112
Ochsner Health System
New Orleans, Louisiana, 70121
New York University Langone Cardiology Associates
New York, New York, 10016
Columbia University Irving Medical Center
New York, New York, 10034
Weill Cornell Medicine Cardiology
New York, New York, 10065
Penn Presbyterian Medical Center
Philadelphia, Pennsylvania, 19104
Mayo Clinic - Arizona
Phoenix, Arizona, 85054
University of Pittsburgh Medical School
Pittsburgh, Pennsylvania, 15261
Oregon Health and Science University
Portland, Oregon, 97239
Virginia Commonwealth University (VCU)
Richmond, Virginia, 23298
Mayo Clinic - Rochester
Rochester, Minnesota, 55905
Laurelton Heart Specialists
Rosedale, New York, 11422
University of Utah
Salt Lake City, Utah, 84112
University of California, San Francisco (UCSF) - Medical Center
San Francisco, California, 94143
University of Washington
Seattle, Washington, 98195
Barnes-Jewish Hospital
St Louis, Missouri, 63110
Stanford Hospital
Stanford, California, 94305
MedStar Washington Hospital Center
Washington D.C., District of Columbia, 20010
The George Washington Medical Faculty Associates - Foggy Bottom North Pavilion
Washington D.C., District of Columbia, 20037
Cleveland Clinic Florida
Weston, Florida, 33331
Japan12 sites
Saiseikai Fukuoka General Hospital
Fukuoka, Hukuoka, 810-0001
Hamamatsu University Hospital
Hamamatsu, Shizuoka, 431-3192
Hospital of the University of Occupational and Environmental Health
Kitakyushu-shi, Fukuoka, 807-8555
Kumamoto University Hospital
Kumamoto, 860-8556
Kurume University Hospital
Kurume-shi, Fukuoka, 830-0011
University Hospital Kyoto Prefectural University of Medicine
Kyoto, Kyoto, 602-8566
Shinshu University Hospital
Matsumoto, Nagano, 390-8621
Okayama University Hospital
Okayama, Okayama-ken, 700-8558
Osaka Metropolitan University Hospital
Osaka, Osaka, 545-8586
Sapporo Medical University Hospital
Sapporo, Hokkaido, 060-8543
Keio University Hospital
Shinjuku-Ku, Tokyo, 160-8582
Uwajima City Hospital
Uwajima-shi, Ehime, 798-8510
Australia8 sites
Box Hill Hospital
Box Hill, Victoria, 3128
Royal Hobart Hospital
Hobart, Tasmania, 7000
Advara HeartCare
Joondalup, Western Australia, 6027
Advara Heartcare
Leabrook, South Australia, 5068
Liverpool Hospital
Liverpool, New South Wales, 2170
Advara HeartCare Murdoch
Murdoch, Western Australia, 6150
The Westmead Institute for Medical Research
Westmead, New South Wales, NSW 2145
Princess Alexandra Hospital
Woolloongabba, Queensland, 4102
United Kingdom8 sites
Synexus - Wales
Cardiff, Wales, CF15 9SS
Synexus Midlands Clinical Research Centre
Edgbaston, B15 2SQ
Synexus - Scotland Clinical Research Centre
Glasgow, Scotland, G20 0SP
Synexus - North Tees Clinical Research Centre
Hexham, TS19 8PE
Synexus - Manchester Clinical Research Centre
Liverpool, L22 0LG
Synexus - Merseyside Clinical Research Centre
Liverpool, L22 0LG
Royal Free London NHS Foundation Trust
London, HR3M+6R
Richmond Pharmacology
London, SE1 1YR
Brazil7 sites
Universidade Estadual de Campinas
Campinas, 13083881
Hospital Moinhos de Vento
Porto Alegre, 90560-030
Centro Avançado de Pesquisa e Estudos para o Diagnóstico CAPED
Ribeirão Preto, 14026-900
Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto
Ribeirão Preto, 14040-030
A Beneficência Portuguesa de São Paulo - Unidade Mirante
São Paulo, 01323-030
Instituto Dante Pazzanese de Cardiologia
São Paulo, 04012-909
Instituto do Coração de São Paulo
São Paulo, 05403-000
Italy7 sites
Azienda Ospedaliero Universitaria Delle Marche
Ancona, 60126
Azienda Ospedaliero-Universitaria di Bologna Policlinico Sant Orsola-Malpighi
Bologna, 40138
Azienda Ospedaliero - Universitaria Careggi
Florence, 50139
Azienda Ospedale - Università di Padova
Padua, 35128
Fondazione IRCCS Policlinico San Matteo
Pavia, 27100
Fondazione Toscana Gabriele Monasterio per la Ricerca Medica e di Sanita Pubblica
Pisa, 56126
Azienda Ospedaliera - Universitaria Sant' Andrea
Roma, 00189
Canada6 sites
University of Calgary
Calgary, Alberta, T2N 4Z6
University Hospital - London Health Sciences Centre
London, Ontario, N6A 5A5
Centre Hospitalier de l'Université de Montréal (CHUM)
Montreal, Quebec, H2X 0C1
Hôpital Regional de Rimouski
Rimouski, Quebec, G5L 5T1
Toronto General Hospital
Toronto, Ontario, M5G 2M9
Gordon and Leslie Diamond Health Care Centre
Vancouver, British Columbia, V5Z 1M9
France6 sites
Hôpitaux Universitaires Henri Mondor
Créteil, 94010
Centre Hospitalier Départemental Vendée
La Roche-sur-Yon, 85925
Hôpital de la Timone
Marseille, 13005
Hôpital Haut-Lévêque
Pessac, 33604
Centre Hospitalier Universitaire De Nantes - Hôpital Nord Laennec
Saint-Herblain, 44805
Hôpital Rangueil
Toulouse, Occitanie, 31059
Germany5 sites
Uniklinik Koln
Cologne, 50937
Universitaetsklinikum Heidelberg - Zentrum fur Innere Medizin
Heidelberg, 69120
Universitätsklinikum des Saarlandes
Homburg, Saarland, 66421
Universitätsklinikum Münster
Münster, 48149
Universitätsklinikum Würzburg
Würzburg, 97078
Portugal4 sites
Hospital da Senhora da Oliveira - Guimarães
Guimarães, 4835-044
Centro Hospitalar Universitário de Lisboa Central - Hospital de Santa Marta
Lisbon, 1169-024
Centro Hospitalar Universitário do Porto - Hospital Geral de Santo Antonio
Porto, 4099-001
Centro Hospitalar Universitário de São João
Porto, 4200-319
Spain4 sites
Hospital Universitari Vall d'Hebrón
Barcelona, 08035
Hospital Universitario Puerta de Hierro - Majadahonda
Majadahonda, 28222
Hospital Clínico Universitario Virgen de la Arrixaca
Murcia, 30120
Complejo Hospitalario Universitario de Santiago
Santiago de Compostela, 15706
Austria3 sites
Medizinische Universität Graz
Graz, Styria, 8036
Medizinische Universität Innsbruck
Innsbruck, Tyrol, 6020
Medizinische Universität Wien
Vienna, 1090
Czechia3 sites
Fakultní Nemocnice u sv. Anny v Brn
Brno, South Moravian, 656 91
Vseobecna Fakultni Nemocnice v Praze
Prague, 128 08
Institut Klinické a Experimentální Medicíny
Prague, 140 21
Israel3 sites
Rambam Health Care Campus
Haifa, 3109601
Hadassah University Hospital Ein Kerem
Jerusalem, 9112001
Kaplan Medical Center
Rehovot
Argentina2 sites
Instituto Cardiovascular de Buenos Aires
Ciudad Autonoma de Buenos Aires, Buenos Aires, C1428ART
Hospital Italiano de Buenos Aires
Ciudad Autónoma de Buenos Aires, Buenos Aires, C1199ABB
Belgium2 sites
Algemeen Ziekenhuis Sint-Jan Brugge-Oostende - Campus Sint-Jan
Bruges, West-Vlaanderen, 8000
Ziekenhuis Oost-Limburg - Campus Sint-Jan
Genk, Limburg, 3600
Denmark2 sites
Rigshospitalet
Copenhagen, Capital Region, 2100
Odense Universitetshospital
Odense, Region Syddanmark, 5000
Poland2 sites
Krakowski Szpital Specjalistyczny im. Jana Pawa II
Krakow, 31-202
Narodowy Instytut Kardiologii Stefana kardyna Wyszyskiego - Pastwowy Instytut Badawczy
Warsaw, 04-628
Sweden2 sites
Sahlgrenska Universitetssjukhuset
Gothenburg, 413 45
Skellefteå lasarett
Skellefteå, 931 86
Puerto Rico1 site
Veterans Affairs Caribbean Healthcare System
San Juan, 00921
About this study
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)
To evaluate the efficacy of eplontersen compared to placebo in participants with ATTR-CM receiving available standard of care (SoC).
Read the detailed description
This is a multicenter, double-blind study in 1438 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.
- Being tested
- Eplontersen, Placebo
- Keywords
- TTR, Amyloidosis, Cardiomyopathy
- Medical subject headings
- Amyloidosis, Cardiomyopathies
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
EplontersenDrug
Also called ION-682884, IONIS-TTR-LRx
Eplontersen by subcutaneous injection
PlaceboDrug
Eplontersen-matching placebo by subcutaneous injection
| Study group | Role | What they receive |
|---|---|---|
| Eplontersen | Experimental | Eplontersen by subcutaneous injection once every 4 weeks Receives: Drug: Eplontersen |
| Placebo | Placebo comparator | Eplontersen-matching placebo by subcutaneous injection once every 4 weeks Receives: Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
Composite Outcome of Cardiovascular (CV) Mortality and Recurrent CV Clinical Events up to Week 140
Measured: Baseline up to Week 140
Secondary outcomes (8)
Change From Baseline in the 6-minute Walk Test (6MWT) Distance at Week 140
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.
Measured: Baseline to Week 140
Change From Baseline in the Kansas City Cardiomyopathy Questionnaire (KCCQ) Scores at Week 140
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.
Measured: Baseline to Week 140
Recurrent CV Clinical Events up to Week 140
Measured: Baseline up to Week 140
All-Cause Mortality up to Week 160
Measured: Baseline up to Week 160
All-Cause Mortality up to Week 140
Measured: Baseline up to Week 140
Composite Outcome of Cardiovascular (CV) Mortality and Recurrent CV Clinical Events up to Week 140 in Subgroup of Patients Treated with Tafamidis at Baseline
To evaluate the effect of treatment with ION-682884 compared to placebo up to Week 140 on the composite endpoint of CV death and recurrent CV clinical events in patients with ATTR-CM on tafamidis at Baseline.
Measured: Baseline up to Week 140
CV Mortality up to Week 160
Measured: Baseline up to Week 160
CV Mortality up to Week 140
Measured: Baseline up to Week 140
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted23 Oct 2019
- Study start13 Mar 2020
- Primary completion25 Mar 2026
- Study completion12 Aug 2026
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (5)Papers the sponsor has linked to this study.
- Other trials for Transthyretin-Mediated Amyloid Cardiomyopathy (ATTR CM)Studies of the same condition, open and under way.
- More trials run by Ionis Pharmaceuticals, Inc.The sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind
- Who is masked
- Participant, Investigator
- Enrolment
- 1,438 participants (actual)
Sponsor and investigators
- Lead sponsor
- Ionis Pharmaceuticals, Inc.
- Sponsor type
- Industry (pharma, biotech, devices)
- Collaborators
- AstraZeneca
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04136171
- Sponsor's protocol ID
- ION-682884-CS2
- Other IDs
- 2019-002835-27, 2024-514434-20-00, 2019
- Status last verified
- Sep 2026
- First submitted
- 21 Oct 2019
- Last updated
- 3 Sep 2026
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Yes: Ionis may share anonymized individual participant data, aggregated clinical data, and other types of data that support the results in this study. Data requests from qualified researchers will be considered once all three of the following criteria are met: (1) 12 months from marketing approval of the study drug in both the United States and European Union; (2) 18 months from conclusion of the study; and (3) 6 months from publication of study article. Access would be via a secure environment and is contingent upon approval of a research proposal and entry into an appropriate data use agreement. Requests to access data can be submitted via the website https://vivli.org/ourmember/ionis/.
Publications
Garcia-Pavia P, Cappelli F, Davis MK, Fontana M, Gillmore JD, Hanna M, Masri A, Obici L, Solomon SD, Sperry BW, Tahara N, Waddington-Cruz M, Boman K, Cuddy SAM, Debonnaire P, Fine NM, Podolec P, Yilmaz A, Conrad T, Yang Q, Claggett BL, Chen J, Tsimikas S, Maurer MS. Eplontersen with and without background transthyretin stabilizers in transthyretin amyloid cardiomyopathy: secondary analysis of a phase 3, randomized controlled trial. Nat Med. 2026 Aug 30. doi: 10.1038/s41591-026-04670-6. Online ahead of print.
PubMed 42742182Gillmore JD, Hamatani Y, Fontana M, Vaduganathan M, Claggett BL, Garcia-Pavia P, Masri A, Cappelli F, Grogan M, Morbach C, Maurer MS, Solomon SD. Gene Silencer Therapy in Transthyretin Amyloid Cardiomyopathy: A Meta-Analysis of Outcomes Trials. JAMA. 2026 Aug 30. doi: 10.1001/jama.2026.17246. Online ahead of print.
PubMed 42669065Fontana M, Masri A, Solomon SD, Cappelli F, Davis MK, Garcia-Pavia P, Gillmore JD, Hanna M, Obici L, Sperry BW, Tahara N, Waddington-Cruz M, Azevedo O, Damy T, de Barros Correia E, Khouri MG, Nikolova AP, Stork S, Conrad T, Yang Q, Claggett BL, Chen J, Brice GT, Tsimikas S, Maurer MS; CARDIO-TTRansform Investigators. Eplontersen for Transthyretin Amyloid Cardiomyopathy. N Engl J Med. 2026 Aug 28. doi: 10.1056/NEJMoa2608510. Online ahead of print.
PubMed 42663301Masri A, Cappelli F, Davis MK, Fontana M, Garcia-Pavia P, Gillmore JD, Hanna M, Obici L, Solomon SD, Sperry BW, Tahara N, Waddington-Cruz M, Kristen AV, Falk RH, Shah SJ, Nativi-Nicolau J, Viney NJ, Yang Q, Chen J, Tsimikas S, Maurer MS. Rationale and Design of CARDIO-TTRansform, a Phase 3 Trial of Eplontersen in Transthyretin Amyloid Cardiomyopathy. Circ Heart Fail. 2026 Jun;19(6):e014205. doi: 10.1161/CIRCHEARTFAILURE.126.014205. Epub 2026 May 9.
PubMed 42104840Masri A, Maurer MS, Claggett BL, Kulac I, Waddington Cruz M, Conceicao I, Weiler M, Berk JL, Gertz M, Gillmore JD, Rush S, Chen J, Zhou W, Kwoh J, Duran JM, Tsimikas S, Solomon SD. Effect of Eplontersen on Cardiac Structure and Function in Patients With Hereditary Transthyretin Amyloidosis. J Card Fail. 2024 Aug;30(8):973-980. doi: 10.1016/j.cardfail.2023.11.016. Epub 2023 Dec 7.
PubMed 38065307