A Study to Evaluate the Efficacy and Safety of Concomitant Use of Eplontersen and ALXN2220 Compared With Eplontersen and Placebo for Adults Participants With ATTR-CM. (ATTRiumph)

A Phase IIb, Randomised, Double-blind, Placebo-controlled, Multicentre Study to Evaluate the Efficacy and Safety of Concomitant Use of Eplontersen and ALXN2220 Compared With Eplontersen and Placebo in Adult Participants With Transthyretin-Mediated Amyloid Cardiomyopathy (ATTR-CM).

The purpose of this randomised, double-blind, placebo-controlled, multicenter study is to evaluate the efficacy and safety of concomitant use of eplontersen and ALXN2220 compared with eplontersen and placebo in adult participants with Transthyretin-mediated amyloid cardiomyopathy (ATTR-CM).

Study Overview

• Status: Not yet recruiting
• Conditions: Transthyretin Amyloid Cardiomyopathy (ATTR-CM)
• Intervention / Treatment: Drug: Eplontersen; Biological: ALXN2220; Other: Placebo

Detailed Description

This is a Phase IIb, multicenter, double-blind study in 326 participants, who will be randomized to receive either eplontersen and ALXN2220 or eplontersen and placebo once every four weeks. Participants will also receive daily supplemental doses of the recommended daily allowance of vitamin A.

• Study Type: Interventional
• Enrollment (Estimated): 326
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: AstraZeneca Clinical Study Information Center; Phone Number: 1-877-240-9479; Email: information.center@astrazeneca.com

Study Locations

• Canada
  • Alberta
    • Calgary, Alberta, Canada, T2N 2T9
      • Research Site
  • British Columbia
    • Vancouver, British Columbia, Canada, V6Z 1Y6
      • Research Site
  • Nova Scotia
    • Halifax, Nova Scotia, Canada, B3H 3A7
      • Research Site
  • Ontario
    • London, Ontario, Canada, N6C 2R5
      • Research Site
    • Toronto, Ontario, Canada, M5G 2C4
      • Research Site
  • Quebec
    • Montreal, Quebec, Canada, H1T 1C8
      • Research Site
• China
  • Beijing, China, 100730
    • Research Site
  • Beijing, China, 100034
    • Research Site
  • Changsha, China, 410012
    • Research Site
  • Chongqing, China, 400042
    • Research Site
  • Guangzhou, China, 510080
    • Research Site
  • Hangzhou, China, 310009
    • Research Site
• France
  • Créteil, France, 94010
    • Research Site
  • Marseille, France, 13005
    • Research Site
  • Rennes, France, 35033
    • Research Site
  • Toulouse, France, 31059
    • Research Site
• Germany
  • Bad Krozingen, Germany, 79189
    • Research Site
  • Berlin, Germany, 10117
    • Research Site
  • Cologne, Germany, 50937
    • Research Site
  • Essen, Germany, 45147
    • Research Site
  • Hamburg, Germany, 22767
    • Research Site
  • Heidelberg, Germany, 69120
    • Research Site
  • Homburg, Germany, 66421
    • Research Site
  • München, Germany, 81377
    • Research Site
  • Münster, Germany, 48149
    • Research Site
• Italy
  • Bologna, Italy, 40138
    • Research Site
  • Florence, Italy, 50134
    • Research Site
  • Milan, Italy, 20138
    • Research Site
  • Padova, Italy, 35128
    • Research Site
  • Pavia, Italy, 27100
    • Research Site
  • Pisa, Italy, 56124
    • Research Site
  • Torino, Italy, 10154
    • Research Site
  • Torrette - Ancona, Italy, 60126
    • Research Site
  • Trieste, Italy, IT-34149
    • Research Site
• Japan
  • Bunkyō City, Japan, 113-8431
    • Research Site
  • Kurume-shi, Japan, 830-0011
    • Research Site
  • Sapporo, Japan, 060-8543
    • Research Site
  • Shinjuku-ku, Japan, 160-8582
    • Research Site
  • Suita, Japan, 565-8565
    • Research Site
• Spain
  • Barcelona, Spain, 08035
    • Research Site
  • Jaén, Spain, 23007
    • Research Site
  • L'Hospitalet de Llobregat, Spain, 08907
    • Research Site
  • Majadahonda, Spain, 28222
    • Research Site
  • Málaga, Spain, 29010
    • Research Site
  • Pamplona, Spain, 31008
    • Research Site
  • Salamanca, Spain, 37007
    • Research Site
  • Valencia, Spain, 46010
    • Research Site
• Sweden
  • Gothenburg, Sweden, 413 45
    • Research Site
  • Lund, Sweden, 22242
    • Research Site
  • Stockholm, Sweden, 171 64
    • Research Site
  • Umeå, Sweden, 90737
    • Research Site
  • Uppsala, Sweden, 751 85
    • Research Site
• United Kingdom
  • London, United Kingdom, NW3 2QG
    • Research Site
  • London, United Kingdom, NW10 2PB
    • Research Site
• United States
  • California
    • La Jolla, California, United States, 92037
      • Research Site
    • San Francisco, California, United States, 94115
      • Research Site
    • Stanford, California, United States, 94305
      • Research Site
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Research Site
  • District of Columbia
    • Washington D.C., District of Columbia, United States, 20010
      • Research Site
  • Florida
    • Jacksonville, Florida, United States, 32224
      • Research Site
    • Miami, Florida, United States, 33176
      • Research Site
    • Weston, Florida, United States, 33331
      • Research Site
  • Illinois
    • Chicago, Illinois, United States, 60637
      • Research Site
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Research Site
  • Missouri
    • Kansas City, Missouri, United States, 64111
      • Research Site
    • St Louis, Missouri, United States, 63110
      • Research Site
  • New York
    • New York, New York, United States, 10032
      • Research Site
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599
      • Research Site
    • Durham, North Carolina, United States, 27710
      • Research Site
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Research Site
  • Oregon
    • Portland, Oregon, United States, 97239
      • Research Site
  • Pennsylvania
    • Danville, Pennsylvania, United States, 17822
      • Research Site
    • Philadelphia, Pennsylvania, United States, 19104
      • Research Site
  • Tennessee
    • Germantown, Tennessee, United States, 38138
      • Research Site
  • Texas
    • Dallas, Texas, United States, 75390
      • Research Site
    • Houston, Texas, United States, 77030
      • Research Site
  • Utah
    • Salt Lake City, Utah, United States, 84132
      • Research Site
  • Virginia
    • Falls Church, Virginia, United States, 22042
      • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Capable of giving informed consent.

Inclusion Criteria:

• Participant must be ≥ 18 years to ≤ 85 years at the time of signing the informed consent.

• Participants who have a diagnosis of ATTR-CM with either wild-type or variant TTR genotype based on 1 of the following:

  1. Endomyocardial biopsy with confirmatory TTR amyloid typing OR
  2. Grade 2 or 3 cardiac uptake on 99mTc scintigraphy in the absence of monoclonal gammopathy OR
  3. Grade 2 or 3 cardiac uptake on 99mTc scintigraphy AND confirmatory TTR amyloid typing in the presence of monoclonal gammopathy.
• NYHA Class I to III at Screening and life expectancy of ≥ 1 year as per the Investigator's judgement.
• End-diastolic IVST ≥ 12 mm on echocardiography.
• NT-proBNP ≥ 600pg/mL for participants without ongoing atrial fibrillation/flutter at Screening or NT-proBNP ≥ 1200pg/mL for participants with ongoing atrial fibrillation/flutter at Screening.

• Able to complete symptom-limited maximal CPET at Screening based on the following test criteria:

  1. Able to exercise to near exhaustion during CPET as exhibited by RER ≥ 1.0 during symptom-limited CPET conducted during screening.
  2. If participant does not achieve RER ≥1.0, the CPET may be repeated once, at least 48 hours but less than 2 weeks (but before randomization) after the initial test.
• Treated according to locally recognised guidelines on standard-of-care treatment for patients with HF. Therapy should have been individually optimised and stable for ≥ 4 weeks (except diuretics) and include, unless contraindicated or not tolerated, treatment of high BP (targeting SBP < 130 mmHg as suggested in 2022 American College of Cardiology/American Heart Association/Heart Failure Society of America HF guidelines), and ischaemic heart disease.
• Willingness to adhere to daily self-administered vitamin A supplementation (3000 IU).

Exclusion Criteria:

• Known leptomeningeal amyloidosis.
• Known light chain (AL) or secondary (amyloid A) amyloidosis, or any other form of systemic amyloidosis.
• Cardiomyopathy not primarily caused by ATTR-CM, for example, cardiomyopathy primarily due to hypertension, valvular heart disease, or ischaemic heart disease per Investigator's assessment.
• Acute coronary syndrome, unstable angina, stroke, transient ischaemic attack, coronary revascularisation, cardiac device implantation, cardiac valve repair, or major surgery within 12 weeks of Screening.
• Uncontrolled hypertension (average resting SBP > 160 mmHg or DBP > 100 mmHg at Screening).
• Average resting SBP < 90 mmHg or symptomatic orthostatic hypotension, despite appropriate treatment, at Screening per Investigator's assessment.
• Uncontrolled ventricular clinically significant cardiac arrhythmia, per Investigator's assessment.
• Left ventricular ejection fraction < 30% on echocardiography measured locally at Screening.
• Severe pulmonary impairment (SpO₂ < 92%) defined as resting SpO₂ below 92% on room air, measured by pulse oximetry, indicative of severe lung disease. Participants requiring supplemental oxygen to maintain SpO₂ ≥ 92%.
• Participants with renal failure requiring dialysis.
• History of solid organ transplantation or ventricular assist device or listing for heart transplantation at Screening. Note: prior history of planned corneal transplant is not an exclusion criterion.
• Suspected or known intolerance/allergy to proteins or any components of the study intervention.

• Any of the following results conducted at screening:

  i) Haemoglobin <8g/dL for women or <9g/dL for men. ii) Platelet count <125 X10*9/L or other disorder associated with clinically significant thrombocytopenia.

iii) ALT >2.0 X ULN iv) TBL >2.5 X ULN (participants with known Gilbert's syndrome can be included with TBL >2.5 X ULN as long as direct bilirubin is ≤ 1.5 X ULN) v) Serum retinol level < LLN vi) By CKD-EPI formula, eGFR <20 mL/min/1.73 m2 measured by the central laboratory at Screening.

• Current unstable liver or biliary disease per Investigator's assessment.
• Multiple myeloma, lymphoma, leukemia, or any malignancy or clonal stem cell disorder within the past 5 years (except basal cell or squamous epithelial carcinomas of the skin, melanoma in situ or cervical carcinoma in situ that have been curatively resected, Stage I cancer in remission, or adequately treated prostate cancer stage I, IIA, or IIB with Gleason score ≤ 3+4 and prostate-specific antigen < 20 ng/mL).
• Any prior treatment with an ATTR amyloid depleter or a TTR gene silencing agent approved or in clinical development.
• Participated in a structured exercise training programme within the 1 month prior to Screening or planned to start during the trial.
• Participation in another investigational clinical study or intake of another investigational drug within 30 calendar days or 5 half-lives of the IMP, whichever is longer before signing the ICF.
• Judgement by the Investigator that the participant should not participate in the study if the participant has a known medical or psychological condition or other risk factor that might interfere with the participant's full participation in the study, pose any additional risk for the participant, or confound the assessment of the participant or outcome of the study.
• Previous enrolment or randomisation in the present study.

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: Eplontersen and ALXN2220; Subcutaneous eplontersen and intravenous ALXN2220 every 4 weeks	Drug: Eplontersen; Eplontersen delivered subcutaneously, once every 4 weeks; Biological: ALXN2220; ALXN2220 delivered intravenously, once every 4 weeks
Placebo Comparator: Eplontersen and placebo; Subcutaneous eplontersen and intravenous placebo every 4 weeks	Drug: Eplontersen; Eplontersen delivered subcutaneously, once every 4 weeks; Other: Placebo; Placebo delivered intravenously, once every 4 weeks

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
CPET peak VO2	Change from baseline in CPET peak VO2 at week 52	52 week

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
ECV	Change from baseline in ECV (subgroup) at week 52	52 week
NT-proBNP	Change from baseline in NT-proBNP at week 52	52 week
Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score	Change from baseline in Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score at week 52. The minimum score is 0 and maximum score is 100. Higher scores indicate better health status.	52 week

Collaborators and Investigators

• Sponsor: AstraZeneca

Study record dates

Study Major Dates

• Study Start (Estimated): June 30, 2026
• Primary Completion (Estimated): February 23, 2029
• Study Completion (Estimated): February 23, 2029

Study Registration Dates

• First Submitted: May 12, 2026
• First Submitted That Met QC Criteria: May 19, 2026
• First Posted (Actual): May 27, 2026

Study Record Updates

• Last Update Posted (Actual): May 27, 2026
• Last Update Submitted That Met QC Criteria: May 19, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: Transthyretin amyloid cardiomyopathy; ATTR-CM; ALXN2220; Eplontersen
• Additional Relevant MeSH Terms: eplontersen
• Other Study ID Numbers: D8456C00001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All request will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

Yes, indicates that AZ are accepting requests for IPD, but this does not mean all requests will be shared.

• IPD Sharing Time Frame: AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
• IPD Sharing Access Criteria: When a request has been approved AstraZeneca will provide access to the de-identified individual patient-level data in an approved sponsored tool . Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

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