E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Transthyretin-Mediated Amyloid Cardiomyopathy (ATTR CM) |
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E.1.1.1 | Medical condition in easily understood language |
A condition that causes damage to the heart |
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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 | 100000004849 |
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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 for 120 weeks on the composite endpoint of cardiovascular (CV) death and frequency of CV clinical events in patients with transthyretin-mediated amyloid cardiomyopathy (ATTR-CM) receiving available standard of care (SoC).
To evaluate the effect of treatment with ION‑682884 compared to placebo for 60 weeks (Week 61 study visit) on exercise tolerance measured by the 6-minute walk test (6MWT) in patients with ATTR-CM receiving available SoC. |
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E.2.2 | Secondary objectives of the trial |
To evaluate the effect of treatment with ION-682884 compared to placebo for 120 weeks on exercise tolerance and patient reported outcomes in patients with ATTR-CM receiving available SoC.
To evaluate the effect of treatment with ION-682884 compared to placebo for 120 weeks on the rates of CV death, CV clinical events, and all-cause death in patients with ATTR-CM receiving available SoC. |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
CARDIO-TTRansform Magnetic Resonance Imaging (MRI) Sub-study, Original Protocol dated 26 June 2020. To measure the amyloid burden (defined as extracellular volume [ECV] assessed by MRI) over time in a subset of patients enrolled in ION-682884-CS2. |
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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 either requires or required treatment with diuretics for clinical stabilization
• Screening N-terminal prohormone of B-type natriuretic peptide (NTproBNP) ≥ 600 pg/mL by central lab. For patients in atrial fibrillation at screening the eligibility NT-proBNP value is ≥ 1200 pg/mL
• New York Heart Association (NYHA) class I-III
• 6MWT ≥ 150 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
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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 immunoglobulin free light chain ratio < 0.26 and/or > 1.65, 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
• 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)
• Current treatment with diflunisal, doxycycline, and/or nondihydropyridine calcium-channel blocker (e.g.,verapamil, diltiazem). Patients receiving any of these agents must respect a Wash-out Period of 14 days before randomisation.
• 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 (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) |
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E.5 End points |
E.5.1 | Primary end point(s) |
Composite endpoint of CV-mortality and frequency of CV clinical events comparing the 2 study arms at Week 120 study visit using the Finkelstein-Shoenfeld method.
Cardiovascular clinical events include:
-Hospitalization for myocardial infarction (MI)
-Hospitalization for heart failure (HF)
-Hospitalization for arrhythmias
-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’
Interim Analysis Primary Endpoint at Week 61
Change from baseline on the 6MWT comparing the first approximately 370 patients enrolled into the 2 study arms at Week 61 study visit. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Interim Analysis Primary Endpoints at Week 61
Final Analysis Primary Endpoints at Week 120 |
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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 120 study visit
Rates of CV mortality, CV clinical events, and all-cause mortality comparing the 2 study arms at Week 120 study visit |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Final Analysis of Secondary Endpoints at Week 120 |
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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 | 1 |
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 |
Austria |
Belgium |
Brazil |
Canada |
Denmark |
France |
Germany |
Greece |
Israel |
Italy |
Japan |
Portugal |
Spain |
Sweden |
United Kingdom |
United States |
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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
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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 | 6 |
E.8.9.1 | In the Member State concerned days | 0 |
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 |