Transthyretin-Mediated Amyloid Cardiomyopathy (ATTR CM)
Conditions
Keywords
TTR, Amyloidosis, Cardiomyopathy
Brief summary
To evaluate the efficacy of eplontersen compared to placebo in participants with ATTR-CM receiving available standard of care (SoC).
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.
Interventions
DRUGEplontersen
Eplontersen by subcutaneous injection
DRUGPlacebo
Eplontersen-matching placebo by subcutaneous injection
Sponsors
Ionis Pharmaceuticals, Inc.
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 90 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Composite Outcome of Cardiovascular (CV) Mortality and Recurrent CV Clinical Events up to Week 140 | Baseline up to Week 140 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in the 6-minute Walk Test (6MWT) Distance at Week 140 | Baseline to 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. |
| Change From Baseline in the Kansas City Cardiomyopathy Questionnaire (KCCQ) Scores at Week 140 | Baseline to 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. |
| Recurrent CV Clinical Events up to Week 140 | Baseline up to Week 140 | — |
| All-Cause Mortality up to Week 160 | Baseline up to Week 160 | — |
| All-Cause Mortality up to Week 140 | 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 | Baseline up to Week 140 | 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. |
| CV Mortality up to Week 160 | Baseline up to Week 160 | — |
| CV Mortality up to Week 140 | Baseline up to Week 140 | — |
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
Outcome results
None listed