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    Summary
    EudraCT Number:2018-004280-32
    Sponsor's Protocol Code Number:AG10-301
    National Competent Authority:Hungary - National Institute of Pharmacy
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2020-02-19
    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 ConcernedHungary - National Institute of Pharmacy
    A.2EudraCT number2018-004280-32
    A.3Full title of the trial
    A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study of the Efficacy and Safety of AG10 in Subjects with Symptomatic Transthyretin Amyloid Cardiomyopathy (ATTRIBUTE-CM Trial)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Study of the Efficacy and Safety of AG10 in participants with Transthyretin Amyloid Cardiomyopathy (ATTR-CM)
    A.3.2Name or abbreviated title of the trial where available
    Efficacy and Safety of AG10 in Subjects with Transthyretin Amyloid Cardiomyopathy (ATTRIBUTE-CM)
    A.4.1Sponsor's protocol code numberAG10-301
    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 SponsorEidos Therapeutics, 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 supportEidos Therapeutics, Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationEidos Therapeutics, Inc.
    B.5.2Functional name of contact pointDirector, Clinical Operations
    B.5.3 Address:
    B.5.3.1Street Address101 Montgomery Street, Suite 2000
    B.5.3.2Town/ citySan Francisco
    B.5.3.3Post codeCA 94104
    B.5.3.4CountryUnited States
    B.5.4Telephone number0014158871471
    B.5.6E-mailvknobel@eidostx.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 Yes
    D.2.5.1Orphan drug designation numberEU/3/18/2081 - EMA/OD/096/18
    D.3 Description of the IMP
    D.3.1Product nameAG10
    D.3.2Product code AG10 HCL
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNAG10 HCl
    D.3.9.1CAS number 2242751-53-5
    D.3.9.3Other descriptive name3-(3-(3,5-DIMETHYL-1H-PYRAZOL-4-YL)PROPOXY)-4-FLUOROBENZOIC ACID
    D.3.9.4EV Substance CodeSUB193376
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number400
    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 No
    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 placeboFilm-coated tablet
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Symptomatic Transthyretin Amyloid Cardiomyopathy (ATTR-CM)
    E.1.1.1Medical condition in easily understood language
    Symptomatic Transthyretin Amyloid Cardiomyopathy (ATTR-CM) is a rare disease that occurs when a protein, called transthyretin, is accumulated in 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
    Part A: To determine the efficacy of AG10 in the treatment of subjects with symptomatic transthyretin amyloid cardiomyopathy (ATTR-CM) by evaluating the difference between the AG10 and placebo groups in the change from baseline in the Six-Minute Walk test (6MWT)
    Part B: To determine the efficacy of AG10 in the treatment of subjects with symptomatic ATTR-CM by evaluating the difference between the AG10 and placebo groups in the combined endpoint of All-Cause Mortality and the cumulative frequency of cardiovascular (CV)-related hospitalization

    Key Secondary
    Part A: To evaluate the effects of AG10 on quality of life (QoL) in subjects with symptomatic ATTR-CM
    Part B:
    •To evaluate the effects of AG10 on 6MWT
    •To evaluate the effects of AG10 on QoL in subjects with symptomatic ATTR-CM
    E.2.2Secondary objectives of the trial
    Part A:
    •To assess safety and tolerability of AG10 in subjects with symptomatic ATTR-CM
    •To assess the PD effects of AG10 as assessed by circulating prealbumin (transthyretin, TTR) concentration as an in vivo biomarker of stabilization and established ex vivo assays of TTR stabilization

    Part B:
    •To determine the efficacy of AG10 treatment as measured by the components of the primary endpoint
    •To determine the efficacy of AG10 in reducing CV mortality in subjects with symptomatic ATTR-CM
    •To describe the PD properties and the PK-PD relationship of AG10 as assessed by circulating prealbumin (transthyretin, TTR) concentration as an in vivo biomarker of stabilization and established ex vivo assays of TTR stabilization, and correlated with AG10 PK
    •To evaluate the safety and tolerability of AG10 administered for 30 months to subjects with symptomatic ATTR-CM
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    To be eligible to participate in the study, subjects must meet all the following criteria:
    1.Have the ability to understand and sign a written informed consent form, which must be obtained prior to initiation of study procedures.
    2.Be male or female ≥18 to ≤90 years of age.
    3.Have an established diagnosis of ATTR-CM with either wild-type TTR or a variant TTR genotype confirmed by genotyping, based on either
    1. endomyocardial biopsy with mass spectrometric analysis or immunoelectron microscopy, or
    2. positive technetium-99m (99mTc)-pyrophosphate or bisphosphonate scan, combined with accepted laboratory criteria excluding a diagnosis of AL amyloidosis (based on both immunofixation electrophoresis (IFE) of serum and urine, and serum free light chain (sFLC) analysis). Subjects with concurrent monoclonal gammopathy of undetermined significance (MGUS) may require confirmation of the diagnosis of ATTR-CM by endomyocardial biopsy with mass spectrometric analysis or immunoelectron microscopy.
    4.Have
    a.a history of heart failure evidenced by at least one prior hospitalization for heart failure or
    b.clinical evidence of heart failure without prior heart failure hospitalization manifested by signs or symptoms of volume overload or elevated intracardiac pressures (e.g., elevated jugular venous pressure, shortness of breath or signs of pulmonary congestion on x-ray or auscultation, or peripheral edema) or
    c.heart failure symptoms that required or require ongoing treatment with a diuretic.
    5.Have NYHA Class I-III symptoms due to ATTR cardiomyopathy.
    6.Female subjects of childbearing potential who engage in heterosexual intercourse must agree to use highly effective methods of contraception beginning with randomization and continuing for 30 days after the last dose of AG10. A man who is sexually active with a woman of childbearing potential and has not had a vasectomy must agree to use a barrier method of birth control
    7.For subjects taking cardiovascular medical therapy, with the exception of diuretic dosing, must be on stable doses (defined as no greater than 50% dose adjustment and no categorical changes of medications) for at least 2 weeks prior to Screening.
    8.Have completed ≥150 m on the 6MWT on 2 tests prior to randomization.
    9.Must have NT-proBNP levels ≥300 pg/mL at Screening.
    10.Must have LV wall (interventricular septum or LV posterior wall) thickness ≥12 mm as measured by transthoracic echocardiogram (ECHO) or cardiac magnetic resonance (CMR) documented in medical history within 10 years of Screening or at Screening ECHO or CMR.
    E.4Principal exclusion criteria
    Subjects who meet any of the following criteria at the Screening visit will not be eligible to participate in the study:
    1.Acute myocardial infarction, acute coronary syndrome or coronary revascularization within 90 days prior to Screening.
    2. Stroke or TIA within 90 days prior to Screening.
    3.Has hemodynamic instability at Screening or Randomization that, in the judgment of the Investigator, would pose too great a risk for participation in the study.
    4.Is likely to undergo heart transplantation within a year of Screening.
    5.Has confirmed diagnosis of light-chain amyloidosis.
    6.Has abnormal liver function tests at Screening, defined as alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >3 × upper limit of normal (ULN) or total bilirubin >3 × ULN.
    7.Has NT-proBNP levels ≥8500 pg/mL at Screening.
    8.Has estimated glomerular filtration rate (eGFR) by MDRD formula < 15 mL/min/1.73 m2 at Screening.
    9.Known hypersensitivity to study drug (AG10 or placebo), its metabolites, or formulation excipients.
    10.Treatment for ATTR-CM with tafamidis, with marketed drug products lacking a labeled indication for ATTR-CM (e.g., diflunisal, doxycycline), or with natural products or derivatives used as unproven therapies for ATTR-CM (e.g., green tea extract, tauroursodeoxycholic acid [TUDCA]/ursodiol) within 14 days prior to dosing; treatment with patisiran, inotersen, or other gene silencing agent: within 90 days for patisiran, 180 days for inotersen, and 5 half-lives for any other gene silencing agent, prior to dosing. If, during participation in the study, subjects gain access to tafamidis, they will be permitted to initiate therapy with tafamidis as a concomitant medication if they have completed at least 24 months of blinded study therapy
    11.Requires treatment with calcium channel blockers with conduction system effects (e.g., verapamil, diltiazem). The use of dihydropyridine calcium channel blockers is allowed. The use of digitalis will only be allowed if required for management of atrial fibrillation with rapid ventricular response
    12.Females who are pregnant or breastfeeding. Lactating females must agree to discontinue nursing before study drug is administered. A negative urine pregnancy test at Screening and at Randomization are required for female subjects of childbearing potential.
    13.In the judgment of the Investigator or Medical Monitor, has any clinically important ongoing medical condition or laboratory abnormality or condition that might jeopardize the subject’s safety, increase their risk from participation, or interfere with the study.
    14.Participation in another investigational drug or investigational device study within 30 days prior to dosing with potential residual effects that might confound the results of this study.
    15.Has any condition that, in the opinion of the Investigator or Medical Monitor, would preclude compliance with the study protocol such as a history of substance abuse, alcoholism or a psychiatric condition.
    E.5 End points
    E.5.1Primary end point(s)
    Part A Change from baseline to Month 12 of treatment in distance walked during the 6MWT

    Part B A hierarchical combination of All-Cause mortality and CV-related hospitalization over a 30-month period
    E.5.1.1Timepoint(s) of evaluation of this end point
    Part A
    -Distance walked during the 6MWT: Prior to randomization, Month 6, 9, 12
    Part B
    -All-cause mortality and CV-related hospitalization: Month 0-30
    E.5.2Secondary end point(s)
    Key Secondary
    Part A
    -Change from baseline to Month 12 of treatment in Kansas City Cardiomyopathy Questionnaire Overall Score (KCCQ-OS)

    Part B:
    -Change from baseline to Month 30 of treatment in distance walked during the 6MWT
    -Change from baseline to Month 30 of treatment in KCCQ-OS

    Other secondary
    Part A
    -Change from baseline in TTR (prealbumin) level (an in vivo measure of TTR stabilization) and established ex vivo assays of TTR stabilization at Day 28 and subsequent visits
    Part B
    -All-Cause Mortality by Month 30
    -Cumulative frequency of CV-related hospitalization by Month 30
    -CV Mortality by Month 30
    -Change from baseline in TTR (prealbumin) level (an in vivo measure of TTR stabilization) and established ex vivo assays of TTR stabilization
    -Describe the PK-PD relationship of AG10 in adult subjects with symptomatic ATTR-CM in the population PK-PD (PopPK-PD) substudy (ONLY for US and UK)
    E.5.2.1Timepoint(s) of evaluation of this end point
    Key secondary
    Part A
    -KCCQ-OS: Day 1, Month 3, 6, 9, 12
    Part B
    -Distance walked during the 6MWT: Prior to randomization, Month 6, 9, 12, 18, 24, 30
    -KCCQ-OS: Day 1, Month 3, 6, 9, 12, 15, 18, 21, 24, 27, 30

    Other secondary
    Part A
    - TTR (prealbumin) level and ex vivo assays of TTR stabilization: Day 1, Day 28, Month 3, 6, 9, 12

    Part B
    - All-Cause Mortality: Month 0-30
    - Cumulative frequency of CV-related hospitalization: Month 0-30
    - CV Mortality: Month 0-30
    - TTR (prealbumin) level ex vivo assays of TTR stabilization: Day 1, Day 28, Month 3, 6, 9, 12, 15, 18, 21, 24, 27, 30
    - PK PD assessments: Day 1, Day 28, Month 3, 6, 9, 12, 15, 18, 21, 24, 27, 30 (ONLY for US and UK)
    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 No
    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 EEA35
    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
    Belgium
    Brazil
    Canada
    Czech Republic
    Denmark
    Greece
    Hong Kong
    Hungary
    Ireland
    Israel
    Italy
    Korea, Republic of
    Lithuania
    Mexico
    Netherlands
    New Zealand
    Poland
    Portugal
    Russian Federation
    Spain
    Turkey
    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 months6
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years5
    E.8.9.2In all countries concerned by the trial months2
    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: 21
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 489
    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 state30
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 220
    F.4.2.2In the whole clinical trial 510
    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)
    At the end of the treatment, the study doctor may continue to give the subject AG10 as an extension of this study, until AG10 is commercially available for the treatment of subjects with symptomatic Transthyretin Amyloid Cardiomyopathy, unless the study doctor believes it no longer in your best interests, or unless the Sponsor terminates development of the AG10 for the treatment of symptomatic ATTR-CM in your country.
    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 Decision2020-05-28
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-05-18
    P. End of Trial
    P.End of Trial StatusCompleted
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