E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Transthyretin-Mediated Amyloid Cardiomyopathy (ATTR CM) |
|
E.1.1.1 | Medical condition in easily understood language |
A condition that causes damage to the heart |
|
E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10002020 |
E.1.2 | Term | Amyloid cardiomyopathy |
E.1.2 | System Organ Class | 10007541 - Cardiac disorders |
|
E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
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). |
|
E.2.2 | Secondary objectives of the trial |
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. |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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 brain 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
|
|
E.4 | Principal 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 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 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 evidenced by positive tests for HIV antibody and HIV RNA), hepatitis C (as evidenced by positive tests for HCV antibody and HCV RNA) or hepatitis B (as evidenced by a positive test for hepatitis B surface antigen) • History of bleeding, diathesis or coagulopathy (e.g., liver cirrhosis, hematologic malignancy, antiphospholipid antibody syndrome, congenital disorders such as hemophilia A, B, and Von Willebrand disease) |
|
E.5 End points |
E.5.1 | Primary end point(s) |
Composite endpoint of CV death and recurrent CV clinical events comparing the 2 study arms at the end of the 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' |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
Final Analysis Primary Endpoints at Week 140 |
|
E.5.2 | 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 comparing the 2 study arms at the end of the study |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
Final Analysis of Secondary Endpoints at Week 140 |
|
E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 6 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 30 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Argentina |
Australia |
Brazil |
Canada |
Israel |
Japan |
United Kingdom |
United States |
Austria |
Belgium |
Czechia |
Denmark |
France |
Germany |
Greece |
Italy |
Poland |
Portugal |
Spain |
Sweden |
|
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 4 |
E.8.9.1 | In the Member State concerned months | 3 |
E.8.9.1 | In the Member State concerned days | 20 |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 3 |
E.8.9.2 | In all countries concerned by the trial days | 30 |