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    Summary
    EudraCT Number:2012-002465-35
    Sponsor's Protocol Code Number:B3461028
    National Competent Authority:Czechia - SUKL
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2014-06-19
    Trial results View 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 ConcernedCzechia - SUKL
    A.2EudraCT number2012-002465-35
    A.3Full title of the trial
    A multicentre, international, phase 3, double-blind, placebo-controlled, randomized study to evaluate the efficacy, safety and tolerability of daily oral dosing of tafamidis meglumine (PF-06291826) 20 mg or 80 mg in comparison to placebo in subjects diagnosed with transthyretin cardiomyopathy (TTR-CM).
    Multicentrická, mezinárodní, dvojitě zaslepená, placebem kontrolovaná, randomizovaná studie fáze III pro posouzení účinnosti, bezpečnosti a snášenlivosti denního orálního užívání přípravku tafamidis meglumine (PF-06291826) 20 mg, nebo 80 mg v porovnání s placebem u subjektů s diagnostikovanou transthyretinovou kardiomyopatií (TTR-CM)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A double-blind, randomized study looking at the efficacy, safety and tolerability of tafamidis meglumine (PF-06291826) 20 mg or 80 mg compared to placebo when taken daily by oral administration mouth in subjects diagnosed with transthyretin cardiomyopathy (TTR-CM).
    A.4.1Sponsor's protocol code numberB3461028
    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 SponsorPfizer 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 supportPfizer Inc, 235 42nd Street, New York, NY 10017
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationPfizer Inc
    B.5.2Functional name of contact pointClinicaltrials.gov Call Center
    B.5.3 Address:
    B.5.3.1Street Address235 East 42nd Street
    B.5.3.2Town/ cityNew York
    B.5.3.3Post codeNY 10017
    B.5.3.4CountryUnited States
    B.5.4Telephone number0018007181021
    B.5.5Fax number0013037391119
    B.5.6E-mailclinicaltrials.govcallcenter@pfizer.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 Yes
    D.2.1.1.1Trade name Vyndaqel 20 mg soft capsule
    D.2.1.1.2Name of the Marketing Authorisation holderPfizer Limited
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEMA/OD/032/06 & EMA/OD/115/12
    D.3 Description of the IMP
    D.3.1Product nameTafamidis meglumine
    D.3.2Product code PF-06291826-83, Fx-1006A
    D.3.4Pharmaceutical form Capsule, soft
    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 INNTafamidis
    D.3.9.1CAS number 951395-08-7
    D.3.9.2Current sponsor codePF-06291826, Fx-1006A
    D.3.9.3Other descriptive nameTafamidis meglumine 20mg soft gelatin capsules
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number20
    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 placeboCapsule, soft
    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
    Transthyretin amyloid cardiomyopathy (TTR-CM)
    E.1.1.1Medical condition in easily understood language
    A condition characterized by the buildup of abnormal deposits of a protein called amyloid in the body's organs and tissues that include the heart, which can result in worsening of its function
    E.1.1.2Therapeutic area Body processes [G] - Metabolic Phenomena [G03]
    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
    The primary objective of this study is to assess the efficacy of an oral dose of 20 mg or 80 mg tafamidis meglumine soft-gel capsules based on all-cause mortality and on frequency of cardiovascular-related hospitalizations as well as to assess safety and tolerability in comparison to placebo. Tafamidis or placebo will be administered once daily, in addition to standard of care, for 30 months in subjects diagnosed with variant or wild-type TTR cardiomyopathy (TTR-CM).
    E.2.2Secondary objectives of the trial
    Not applicable
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the study:

    1.Evidence of a personally signed and dated Informed Consent Document indicating that the subject (or a legal representative) has been informed of all pertinent aspects of the study and evidence of a personally signed and dated Release of Medical Information Form regarding access to medical records as well as vital status/transplant status follow-up by the site with the subject or the subject’s caregivers 30 months after study randomization. In some cases, sites may combine these two forms into one form, as is their standard practice.

    2. Subjects who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures,

    3. Age greater than or equal to 18 and less than or equal to 90 years old at the time of randomization,

    4. Medical history of Heart Failure (HF) with at least 1 prior hospitalization for HF or clinical evidence of HF (without 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, peripheral edema) that required/requires treatment with a diuretic for improvement,

    5. Subject has documented TTR amyloid cardiomyopathy in accordance with institutional site standard of care, which is defined as:

    a. Variant TTR amyloid cardiomyopathy defined by all of the following:

    i. presence of a variant TTR genotype associated with cardiomyopathy and presenting with a cardiomyopathy phenotype (e.g., a history of congestive heart failure),
    1. TTR genotyping is required at Screening unless documentation (ie original laboratory result, or copy) of a prior determination of a TTR genotype is produced.
    2. Subjects with a confirmed diagnose of mutant (variant genotype) TTR-CM with concurrent monoclonal gammopathy of undetermined significance (MGUS) based on serum or urine light chain determinations, should be tested in the same manner as in the case of equivocal immunohistochemistry for subjects with wild type TTE-CM below.

    ii. evidence of cardiac involvement by echocardiography with an enddiastolic interventricular septal wall thickness > 12 mm,

    iii. presence of amyloid deposits in biopsy tissue, such as fat aspirate, salivary gland, median nerve connective tissue sheath, or cardiac (amyloid demonstrated per appropriate stain such as Congo red or alcian blue stain).

    iv. TTR precursor protein identification by mass spectrometry. (Ruberg and Berk 2012, Dungu et al, 2012).
    1. In the case where immunohistochemistry (IHC) outcome is equivocal such as staining suggestive of lambda or kappa light chains, additional confirmatory testing is required to confirm the diagnosis of TTR cardiomyopathy. This confirmatory test may be performed using one of the following: (a) mass spectrometry (b) immunohistochemistry with electron microscopy or immunoelectron microscopy or immune-gold microscopy (c) scintigraphy with tracer e.g. 99mTC-DPD [99mTC-3,3-diphosphono-1,2-propano-dicarboxylic acid], 99mTC- PYP [Pyrophosphate] and also 99mTC-HMDP [hydroxymethylene diphosphonate](Ando Y 2013. Glaudemans 2014, Bokhari S 2014, Bokhari S 2013).

    b. Wild-type TTR amyloid cardiomyopathy defined by all of the following:

    i. absence of a variant TTR genotype,

    ii. evidence of cardiac involvement by echocardiography with an enddiastolic
    interventricular septal wall thickness > 12 mm,

    iii. presence of amyloid deposits in biopsy tissue, such as fat aspirate, salivary gland, median nerve connective tissue sheath, or cardiac (amyloid demonstrated per appropriate stain such as Congo red or alcin blue stain),

    iv. TTR precursor protein identification by mass spectrometry.

    6. Biopsy used to determine the presence of amyloid and demonstration of TTR precursor protein must be done during Screening or documented as having been performed previously.

    7. Subject must be able to read in native language and complete self-administered questionnaires independently,

    8. Subject’s symptoms of HF are optimally managed and clinically stable with no cardiovascular-related hospitalizations within 2 weeks prior to Baseline, as assessed by the Principal Investigator,

    9. Male and female subjects of childbearing potential and at risk for pregnancy must agree to use two highly effective methods of contraception throughout the study and for at least 28 days after the last dose of assigned treatment. A subject is of childbearing potential if, in the opinion of the investigator, he/she is biologically capable of having children and is sexually active,

    10. Subject must have a Screening visit NT-proBNP concentration ≥ 600 pg/mL (the conversion factor from conventional pg/mL to SI units is to divide by 8.45)

    11. Subjects must be able to complete > 100 m on the 6-Minute Walk Test at screening.
    E.4Principal exclusion criteria
    Subjects presenting with any of the following will not be included in the study:

    1. Subjects with echocardiogram assessment at Screening that is not deemed interpretable by the central echocardiogram reader for the measurement of wall thickness,

    2. Subjects using non-steroidal anti-inflammatory drugs (NSAIDs) that are not allowable in the protocol within 30 days prior to the Baseline visit.

    3. Subjects with an mBMI below 600,

    4. Subjects with a history of drug or alcohol abuse within the past 5 years that in the opinion of the investigator would interfere with compliance with study procedures or follow-up visits,

    5. Subjects taking or have previously taken tafamidis,

    6. Subjects requiring treatment with calcium channel blockers (e.g. verapamil diltiazem) or digitalis,

    7. Subjects with primary (light chain) amyloidosis,

    8. Subjects who have prior liver or heart transplantation or implanted cardiac mechanical assist device,

    9. Subject has known or suspected hepatitis B,C,Human Immunodeficiency Virus (HIV) infection or positive serology for hepatitis B (HBsAg), hepatitis C (anti-HCV), or HIV,

    10. Subjects with renal failure requiring dialysis and/or have an estimated glomerular filtration rate (eGFR) of <25mL/min/1.73

    11. Subjects with urinary retention requiring self-catheterization,

    12. Subjects who are investigational site staff members directly involved in the conduct of the trial and their family members, site staff members otherwise supervised by the Investigator, or subjects who are Pfizer employees directly involved in the conduct of the trial.

    13. Subjects who have symptoms indicative of New York Heart Association Classification IV at the Screening or Baseline visit,

    14. Subjects with liver function test abnormalities (alanine transaminase and/or aspartate transaminase) greater than 2 times the upper limit of normal that are considered to be due to reduced liver function or active liver disease,

    15. Subjects with participation in studies involving investigational drug(s) (Phases 1- 4) within 30 days before the current study begins and/or during study participation. For diflunisal, tauroursodeoxycholate and doxycycline this time period will be within 30 days before the Baseline visit and/or any time during study participation,

    16. Subjects with other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the subject inappropriate for entry into this study,

    17. Subjects who are pregnant females; breastfeeding females; male subjects with partners currently pregnant, males and females of childbearing potential who are unwilling or unable to use two (2) highly effective method of contraception as outlined in this protocol for the duration of the study and for at least 28 days, after last dose of investigational product;

    18. Subjects with a history of sustained ventricular tachycardia or aborted ventricular fibrillation or with a history of atrioventricular (AV) nodal or sinoatrial (SA) nodal dysfunction for which a pacemaker is indicated but will not be placed,

    19. Subjects with evidence for prior myocardial infarction by documented history of cardiac enzymes and ECG changes.
    E.5 End points
    E.5.1Primary end point(s)
    1. All-cause mortality and

    2. Frequency of cardiovascular-related hospitalizations over the duration of the trial, which is defined as the number of times a subject is hospitalized (i.e., admitted to a hospital) for cardiovascular-related morbidity.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Both primary end points will be assessed throughout the study.
    E.5.2Secondary end point(s)
    Key Secondary Endpoints
    1. Change from Baseline to Month 30 in the distance walked during 6-Minute Walk Test (6MWT),

    2. Change from Baseline to Month 30 in the Kansas City Cardiomyopathy Questionnaire Overall Score (KCCQ-OS).

    Other secondary endpoints
    1. Cardiovascular-related mortality,

    2. Frequency of cardiovascular-related hospitalization,

    3. All-cause mortality,

    4. TTR stabilization at Month 1.
    E.5.2.1Timepoint(s) of evaluation of this end point
    1. Distance walked during 6 Minute Walk Test (6MWT) at baseline (Day 1) and Months 6, 12, 18, 24 and 30 or end of treatment.

    2. Kansas City Cardiomyopathy Questionnaire Overall Score (KCCQ-OS) at baseline (Day 1) and Months 6, 12, 18 and 30 or end of treatment.

    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 Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic Yes
    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 trial3
    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
    Belgium
    Brazil
    Canada
    Czech Republic
    France
    Germany
    Italy
    Japan
    Netherlands
    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
    Last subject last visit.
    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 years4
    E.8.9.2In all countries concerned by the trial months6
    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: 40
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 360
    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 state10
    F.4.2 For a multinational trial
    F.4.2.2In the whole clinical trial 400
    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)
    Upon completion of the study at Month 30 visit, subjects will be eligible for open-label treatment with tafamidis in a separate study.
    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 Decision2014-10-08
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2014-10-16
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2018-02-07
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