Transthyretin-Mediated Amyloid Cardiomyopathy (ATTR CM) MedDRA version: 20.0 Level: LLT Classification code 10002020 Term: Amyloid cardiomyopathy System Organ Class: 10007541 - Cardiac disorders
Conditions
Sponsors
Ionis Pharmaceuticals, Inc.
Eligibility
Sex/Gender
All
Inclusion 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 • Willing to be genetically tested for mutations in the transthyretin (TTR) gene during screening, if it was not done before • 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 99mTc-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 mm on Screening echocardiogram • Medical history of heart failure (HF) secondary to hereditary or wild-type ATTR-CM with at least: A) prior hospitalization for HF, which may include hospitalization for arrhythmia or pacemaker/ICD (implantable cardioverter defibrillator) placement, OR B) symptoms and signs of volume overload or elevated intracardiac pressure that requires treatment with diuretics other than mineralocorticoid receptor antagonists (MRA) for clinical stabilization • Screening N-terminal prohormone of B-type natriuretic peptide (NT-proBNP) = 600 pg/mL (= 70 pmol/L) by central lab. For patients in atrial fibrillation at screening the NT-proBNP values = 1200 pg/mL (= 140 pmol/L) • New York Heart Association (NYHA) class I-III • 6MWT = 100 meters • If on medical treatment for HF on stable dosage regimen for 2 weeks prior to randomization • Willingness to adhere to vitamin A supplement per protocol Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 350 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 1050
Exclusion criteria
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 patients with 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 risk 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 RNA therapeutic (including siRNA; does not apply to COVID-19 mRNA vaccinations) • Current treatment with diflunisal, doxycycline, with or without ursodeoxycholic acid, and/or non-dihydropyridine calcium-channel blocker (e.g.,verapamil, diltiazem). Patients receiving any of these agents must respect a Wash-out Period of 14 days before randomization. • Abnormal thyroid function tests with clinical significance per Investigator judgement. • Contraindication for immunosuppressive therapy, per Investigator's discretion • Known history of or positive test for human immunodeficiency virus (HIV) (as evidence by positive test for HIV antibody and HIV RNA), hepatitis C (as evidence by positive tests for HCV antibody and HCV RNA) or hepatitis B (as evidence by a positive test for hepatitis B surface antigen) • History of bleeding, diathesis or coagulophaty (e.g., liver cirrhosis, hematologic malignancy, antiphospholipid antibody syndrome, congenital disorders such as hemophilia A, B, and Von Willebrand disease)
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To evaluate the effect of treatment with ION-682884 compared to placebo at the end of the study on the composite endpoint of cardiovascular (CV) death and recurrent CV clinical events in patients with transthyretin-mediated amyloid cardiomyopathy (ATTR-CM) receiving available standard of care (SoC). ;Secondary Objective: To evaluate the effect of treatment with ION-682884 compared to placebo at Week 121 Study Visit on exercise tolerance (assessed by the 6MWT) and patient reported outcomes (Kansas City Cardiomyopathy Questionnaire [KCCQ]) in patients with ATTR-CM receiving available SoC To evaluate the effect of treatment with ION-682884 compared to placebo at the end of the study of CV clinical events, CV death and all-cause death in patients with ATTR-CM receiving available SoC ;Primary end point(s): Composite endpoint of CV death and recurrent CV clinical events comparing the 2 study arms at the end of study. Cardiovascular clinical events include: -Hospitalization for myocardial infarction (MI) -Hospitalization for heart failure (HF) -Hospitalization for arrhythmias and/or an arrhythmia event requiring medical treatment in outpatient facility or ER -Hospitalization for stroke/ Transient Ischemic Attack (TIA) -HF urgent visits to Emergency Department/Emergency Room (ED/ER) or HF clinics requiring administration of intravenous (IV) diuretics for improvement. All deaths and CV clinical events will be adjudicated by an independent Clinical Adjudication Committee (CAC) using the ‘2017 Cardiovascular and Stroke Endpoint Definitions for Clinical Trials’ ;Timepoint(s) of evaluation of this end point: Final Analysis Primary Endpoints at Week 140 | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Changes from baseline in the 6MWT distance and Kansas City Cardiomyopathy Questionnaire (KCCQ) scores comparing the 2 study arms at Week 121 study visit CV clinical events, CV mortality, and all-cause mortality at the end of the study;Timepoint(s) of evaluation of this end point: Final Analysis of Secondary Endpoints at Week 140 | — |
Countries
Argentina, Australia, Austria, Belgium, Brazil, Canada, Czechia, Czech Republic, Denmark, France, Germany, Greece, Israel, Italy, Poland, Portugal, Spain, Sweden, United Kingdom, United States
Contacts
Public ContactIonis Clinical Trial Information
Ionis Pharmaceuticals, Inc.
Outcome results
None listed