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)

• ClinicalTrials.gov Identifier: NCT04136171
• Recruitment Status: Recruiting
• First Posted: October 23, 2019
• Last Update Posted: March 27, 2023
• Sponsor: Ionis Pharmaceuticals, Inc.
• Information provided by (Responsible Party): Ionis Pharmaceuticals, Inc.

Tracking Information

• First Submitted Date: October 21, 2019
• First Posted Date: October 23, 2019
• Last Update Posted Date: March 27, 2023
• Actual Study Start Date: March 13, 2020
• Estimated Primary Completion Date: June 2025 (Final data collection date for primary outcome measure)
• Current Primary Outcome Measures (submitted: July 15, 2022): Composite Outcome of Cardiovascular (CV) Mortality and Recurrent CV Clinical Events up to Week 140 [ Time Frame: Baseline up to Week 140 ]

Original Primary Outcome Measures (submitted: October 21, 2019)

• Composite Outcome of Cardiovascular (CV) Mortality and frequency of CV clinical events at Week 120 [ Time Frame: Baseline to Week 120 ]
  This composite measure is based on the Finkelstein-Shoenfeld method, with each participant compared with every other participant in a pairwise manner. The test assigns a +1 or a -1 to a participant based on each participant's CV clinical events or mortality. The test statistic is based on the sum of these scores and will be stratified by the stratification factors. The mortality and CV clinical events in all analyses, unless otherwise specified, will be adjudicated by an independent CAC using the '2017 Cardiovascular and Stroke Endpoint Definitions for Clinical Trials'
• Change From Baseline on the 6-Minute Walk Test (6MWT) at Week 61 [ Time Frame: Baseline to Week 61 ]
  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.

Current Secondary Outcome Measures (submitted: July 15, 2022)

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

Original Secondary Outcome Measures (submitted: October 21, 2019)

• Change From Baseline in the 6MWT Distance at Week 120 [ Time Frame: Baseline to Week 120 ]
  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.
• Change From Baseline in the Kansas City Cardiomyopathy Questionnaire (KCCQ) Scores at Week 120 [ Time Frame: Baseline to Week 120 ]
  The Kansas City Cardiomyopathy Questionnaire (KCCQ) is a 23-item self-administered questionnaire developed to independently measure the patient'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.
• Rate of CV Mortality at Week 120 [ Time Frame: Baseline to Week 120 ]
• Rate of CV Clinical Events at Week 120 [ Time Frame: Baseline to Week 120 ]
• Rate of All-Cause Mortality at Week 120 [ Time Frame: Baseline to Week 120 ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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)
• 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.
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Treatment
• Condition: Transthyretin-Mediated Amyloid Cardiomyopathy (ATTR CM)

Intervention

• Drug: Eplontersen
  Eplontersen by subcutaneous injection
  Other Names:

  • ION-682884
  • AKCEA-TTR-LRx
  • IONIS-TTR-LRx
• Drug: Placebo
  Eplontersen-matching placebo by subcutaneous injection

Study Arms

• Experimental: Eplontersen
  Eplontersen by subcutaneous injection once every 4 weeks
  Intervention: Drug: Eplontersen
• Placebo Comparator: Placebo
  Eplontersen-matching placebo by subcutaneous injection once every 4 weeks
  Intervention: Drug: Placebo

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: October 31, 2022): 1400
• Original Estimated Enrollment (submitted: October 21, 2019): 750
• Estimated Study Completion Date: November 2025
• Estimated Primary Completion Date: June 2025 (Final data collection date for primary outcome measure)

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 90 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Ionis Pharmaceuticals; (844) 413-0219; ionisNCT04136171study@clinicaltrialmedia.com

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

Administrative Information

• NCT Number: NCT04136171
• Other Study ID Numbers: ION-682884-CS2; 2019-002835-27 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• 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

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Ionis Pharmaceuticals, Inc.
• Original Responsible Party: Same as current
• Current Study Sponsor: Ionis Pharmaceuticals, Inc.
• Original Study Sponsor: Same as current
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: Ionis Pharmaceuticals, Inc.
• Verification Date: March 2023