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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)

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ClinicalTrials.gov Identifier: NCT04136171
Recruitment Status : Active, not recruiting
First Posted : October 23, 2019
Last Update Posted : January 23, 2024
Sponsor:
Information provided by (Responsible Party):
Ionis Pharmaceuticals, Inc.

Study Description
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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.

Condition or disease Intervention/treatment Phase
Transthyretin-Mediated Amyloid Cardiomyopathy (ATTR CM) Drug: Eplontersen Drug: Placebo Phase 3

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.
Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 1438 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
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)
Actual Study Start Date : March 13, 2020
Estimated Primary Completion Date : June 2025
Estimated Study Completion Date : November 2025

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Experimental: Eplontersen
Eplontersen by subcutaneous injection once every 4 weeks
 Drug: Eplontersen
Eplontersen by subcutaneous injection
Other Names:
  • ION-682884
  • AKCEA-TTR-LRx
  • IONIS-TTR-LRx
Placebo Comparator: Placebo
Eplontersen-matching placebo by subcutaneous injection once every 4 weeks
 Drug: Placebo
Eplontersen-matching placebo by subcutaneous injection


Outcome Measures
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Primary Outcome Measures :
  1. Composite Outcome of Cardiovascular (CV) Mortality and Recurrent CV Clinical Events up to Week 140 [ Time Frame: Baseline up to Week 140 ]

Secondary Outcome Measures :
  1. Change From Baseline in the 6-minute Walk Test (6MWT) Distance at Week 121 [ Time Frame: Baseline to 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.

  2. Change From Baseline in the Kansas City Cardiomyopathy Questionnaire (KCCQ) Scores at Week 121 [ Time Frame: Baseline to 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.


  3. CV Clinical Events up to Week 140 [ Time Frame: Baseline up to Week 140 ]
  4. CV Mortality up to Week 140 [ Time Frame: Baseline up to Week 140 ]
  5. All-Cause Mortality up to Week 140 [ Time Frame: Baseline up to Week 140 ]

Eligibility Criteria
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Ages Eligible for Study:   18 Years to 90 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04136171


Locations
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Sponsors and Collaborators
Ionis Pharmaceuticals, Inc.
More Information
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Additional Information:

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Responsible Party: Ionis Pharmaceuticals, Inc.
ClinicalTrials.gov Identifier: NCT04136171    
Other Study ID Numbers: ION-682884-CS2
2019-002835-27 ( EudraCT Number )
First Posted: October 23, 2019    Key Record Dates
Last Update Posted: January 23, 2024
Last Verified: January 2024
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
Keywords provided by Ionis Pharmaceuticals, Inc.:
TTR
Amyloidosis
Cardiomyopathy
Additional relevant MeSH terms:
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Cardiomyopathies
Amyloidosis
Heart Diseases
 Cardiovascular Diseases
Proteostasis Deficiencies
Metabolic Diseases