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    Summary
    EudraCT Number:2019-002835-27
    Sponsor's Protocol Code Number:ION-682884-CS2
    National Competent Authority:France - ANSM
    Clinical Trial Type:EEA CTA
    Trial Status:Trial now transitioned
    Date on which this record was first entered in the EudraCT database:2020-12-07
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedFrance - ANSM
    A.2EudraCT number2019-002835-27
    A.3Full title of the trial
    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)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A global trial to determine the effectiveness and safety of ION-682884 in patients with Transthyretin-Mediated Amyloid Cardiomyopathy (ATTR CM)
    A.3.2Name or abbreviated title of the trial where available
    CARDIO –TTRANSFORM
    A.4.1Sponsor's protocol code numberION-682884-CS2
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT04136171
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorIonis Pharmaceuticals, Inc.
    B.1.3.4CountryUnited States
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportIonis Pharmaceuticals, Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationIonis Pharmaceuticals, Inc.
    B.5.2Functional name of contact pointIonis Clinical Trial Information
    B.5.3 Address:
    B.5.3.1Street Address2855 Gazelle Court
    B.5.3.2Town/ cityCarlsbad
    B.5.3.3Post codeCA 92010
    B.5.3.4CountryUnited States
    B.5.4Telephone number+1760603 3890
    B.5.5Fax number+1760603 2504
    B.5.6E-mailClinicalTrials@ionisph.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameION-682884
    D.3.2Product code ION-682884
    D.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNnot available
    D.3.9.1CAS number 1637600-16-8
    D.3.9.2Current sponsor codeION-682884
    D.3.9.3Other descriptive nameAKCEA-TTR-LRx
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number150
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product Yes
    D.3.11.13.1Other medicinal product typeAntisense Oligonucleotide
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboSolution for injection
    D.8.4Route of administration of the placeboSubcutaneous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Transthyretin-Mediated Amyloid Cardiomyopathy (ATTR CM)
    E.1.1.1Medical condition in easily understood language
    A condition that causes damage to the heart
    E.1.1.2Therapeutic area Diseases [C] - Cardiovascular Diseases [C14]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10002020
    E.1.2Term Amyloid cardiomyopathy
    E.1.2System Organ Class 100000004849
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main 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.
    E.2.2Secondary 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.
    E.2.3Trial contains a sub-study No
    E.3Principal 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 brain natriuretic peptide (NT-proBNP) ≥ 600 pg/mL by central lab. For participants in atrial fibrillation at screening the eligibility range 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
    E.4Principal 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
    • Screening laboratory results as follows, or any other clinically significant abnormalities in Screening laboratory values that would render a patient unsuitable for inclusion
    a. Alanine aminotransferase/aspartate aminotransferase (ALT/AST) > 2.0 × upper limit of normal (ULN)
    b. Total bilirubin ≥ 1.5 × ULN (patients with total bilirubin ≥ 1.5 × ULN may be allowed on study if indirect bilirubin only is elevated, ALT/AST is not greater than the ULN, and known to have Gilbert’s disease)
    c. Platelets < lower limit of normal (LLN; central laboratory)
    d. Urine protein creatinine ratio (UPCR) ≥ 750 mg/g. In the event of UPCR above this threshold, ineligibility may be confirmed by a repeat random spot UPCR ≥ 750 mg/g
    e. Positive test for blood (including trace) on urinalysis that is subsequently confirmed with urine microscopy showing > 5 red blood cells per high power field and is related to glomerulopathies. In women, this exclusion criterion must be assessed outside of menstrual period. If in the opinion of the Investigator the haematuria is not considered related to glomerulopathies the patient may be considered eligible, pending proper follow-up and a discussion with the medical monitor. Patients with history of bladder cancer must have been treated with curative intent and have not presented recurrence within the prior 5 years.
    f. Estimated glomerular filtration rate (eGFR) < 45 mL /min/1.73 m2 at Screening [CKD-EPI formula; (Levey et al. 2009)]. If the eGFR is thought to be underestimated, the CKD EPI creatinine cystatin C equation can be used for confirmation (Inker et al. 2012)
    g. Abnormal thyroid function tests with clinical significance per Investigator judgement
    h. Serum retinol level at Screening < LLN (this criterion does not apply to hATTR CM patients with mutation at the position 84 [e.g., Ile84Ser])
    i. Hemoglobin A1c (HbA1c) > 9.5%
    • 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 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
    (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)
    • If receiving oral anticoagulants, (except vitamin K antagonists) the dose must have been stable for 4 weeks prior to the first dose of Study Drug and regular monitoring must be performed, per clinical practice, during the study. If the patient is receiving vitamin K antagonists (e.g., warfarin) INR should be in therapeutic range, as established by the Investigator, for 4 weeks prior to the first dose.
    Known history of sustained ventricular tachycardia or aborted ventricular fibrillation
    • Known history of atrioventricular nodal or sinoatrial nodal dysfunction for which a pacemaker is indicated but will not be placed
    • Known history of multiple drug allergies or history of allergic reaction to an oligonucleotide or GalNAc
    • Known intolerance to SC injections
    • Untreated hypo- or hyperthyroidism
    • New York Heart Association (NYHA) class IV
    • Severe hepatic impairment
    E.5 End points
    E.5.1Primary 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.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Interim Analysis Primary Endpoints at Week 61

    Final Analysis Primary Endpoints at Week 120
    E.5.2Secondary 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
    E.5.2.1Timepoint(s) of evaluation of this end point
    Final Analysis of Secondary Endpoints at Week 120
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    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.8.4.1Number of sites anticipated in Member State concerned3
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA30
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If 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
    E.8.7Trial 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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    E.8.9.1In the Member State concerned months3
    E.8.9.1In the Member State concerned days30
    E.8.9.2In all countries concerned by the trial years4
    E.8.9.2In all countries concerned by the trial months3
    E.8.9.2In all countries concerned by the trial days30
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 187
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 563
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state50
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 150
    F.4.2.2In the whole clinical trial 750
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    After completion of the Treatment Period, eligible patients may elect to receive ION-682884 in an open-label extension (OLE) study, pending study approval by the Institutional review Board/Independent Ethics Committee (IRB/IEC) and the appropriate regulatory authority. In this case, patients will not participate in the Post-Treatment Evaluation period assessments. All participating patients in the OLE study will receive ION‑682884 SC once every 4 weeks.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2020-11-13
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2021-03-31
    P. End of Trial
    P.End of Trial StatusTrial now transitioned
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